Compositions comprising lipophilic active compounds and method for their preparation

ABSTRACT

Compositions are provided comprising a lipophilic active compound, e.g., a human or veterinary drug or a nutraceutical, interwoven with a polymeric matrix formed by two or more polymers, wherein one of the polymers is an amphiphilic polymer and the other polymer is either an amphiphilic polymer with a different hydrophobic-hydrophilic balance or a hydrophilic polymer, and the active lipophilic compound has modified physicochemical properties. The composition forms colloidal nanodispersion upon contact with aqueous media.

FIELD OF THE INVENTION

The present invention relates to compositions comprising lipophilicactive compounds and polymers, and more particularly to pharmaceuticalcompositions comprising lipophilic drugs for oral administration.

BACKGROUND OF THE INVENTION

Lipophilic drug substances having low water solubility are a growingclass of drugs with increasing applicability in a variety of therapeuticareas for a variety of pathologies. Many compounds approved forpharmaceutical use are lipophilic compounds with limited solubility andbioavailability. Relatively insoluble compounds, i.e., solubility inwater of less than 200 μg/ml, may show promising pharmaceuticalactivity, but their development as pharmaceuticals, particularly in oraldosage form, present a significant challenge to the pharmaceuticalindustry.

Among the main barriers for effective drug delivery are solubility andstability. To be absorbed in the human body, a compound has to besoluble in both water and fats (lipids). However, solubility in water isoften associated with poor fat solubility and vice-versa.

Solubility and stability are, therefore, major obstacles hindering thedevelopment of therapeutic agents. Aqueous solubility is a necessary butfrequently elusive property for formulations of the complex organicstructures found in pharmaceuticals. Traditional formulation systems forvery insoluble drugs have involved a combination of organic solvents,surfactants and extreme pH conditions. These formulations are oftenirritating to the patient and may cause adverse reactions. At times,these methods are inadequate for solubilizing enough of a quantity of adrug for a parenteral formulation.

Bioavailability refers to the degree to which a drug becomes availableto the target tissue or any alternative in vivo target (i.e., receptors,tumors, etc.) after being administered to the body. Poor bioavailabilityis a significant problem encountered in the development ofpharmaceutical compositions, particularly those containing an activeingredient that is poorly soluble in water. Poorly water-soluble drugstend to be eliminated from the gastrointestinal tract before beingabsorbed into the circulation.

In order to increase the solubility of poorly soluble drugs, severaltechniques have been used such as (i) selection of more solublepolymorphs, hydrates or salts; (ii) addition of additives as surfactantsto solubilize the drug; and (iii) use of particle size reduction (e.g.,micronization) which increases the area of drug in contact with themedium, to accelerate dissolution. These techniques, however, weresometimes inadequate to provide satisfactory solubility.

More sophisticated solubilization approaches have been developed inrecent years, based on; (i) a new generation of size reductiontechnology; (ii) advanced solubilizing agents that “drag” the insolubledrug into solution and increase the miscibility of the drug with aqueousmedia.; and (iii) use of amorphous forms or eutectic mixtures to reducethe thermodynamic barriers to dissolution

With regard to the size reduction, it is known that the rate ofdissolution of a particulate drug can increase with increasing surfacearea, namely, decreasing particle size. It is generally accepted thatwater insoluble or poorly water-soluble drugs can be made morebioavailable when presented in the form of small particles. The newtechniques for size reduction reduce the particle size to a much greaterextent than ever previously seen; hence the micronization of the pasthas been replaced by new technologies that produce nanoparticles, whichare up to 1000 times smaller. Above and beyond the dramatic increase insurface area seen with nanoparticles (and the consequent effects on therate of dissolution), it has been suggested that the use of particles inthe nanosize range may even increase the saturation solubility of a drugin an aqueous medium and allow local supersaturation.

Nanoparticles can be generated by many different means, such as sizereduction by advanced milling techniques or by precipitation. However,after the formation of the drug nanoparticles, many of these techniquesface a common problem: the tendency of very small drug particles toagglomerate together. Many of the inventions in the field focus onpreventing this agglomeration, often by coating the nanoparticles

A number of solubilization technologies for water-insoluble drugs existsuch as nanosuspensions, nanoparticles, liposomes, cyclodextrins,dendrimers, micro- and nanoencapsulation, and solid dispersion, but eachof these technologies has a number of significant disadvantages.

One of the methods employed to increase the surface area of particlesand thus enhance the solubility of water-insoluble compounds in drugformulations is to make a solid dispersion of insoluble pharmaceuticalsubstances in high molecular weight water-soluble polymeric matrices,which act as a solubility bridge between the insoluble compound and anaqueous medium (Christian Leuner and Jennifer Dressman, 2000, Improvingdrug solubility for oral delivery using solid dispersions, EuropeanJournal of Pharmaceutics and Biopharmaceutics, 50:47-60). A soliddispersion always contains at least two components: a matrix and a drug.The matrix can be either amorphous or crystalline, and the drug can bedispersed within the matrix as a molecular dispersion or as nanosizedcrystals or as amorphous particles. It is currently not clear how thecomplex interactions between drug-matrix and aqueous solvent improve thesolubility of the drug.

Solid dispersions are physico-chemically classified as eutectics, solidsolutions, glass solutions, glass suspensions, amorphous precipitate ina glassy or crystalline carrier, complex formation and/or a combinationof the different systems. With the proper choice of polymers it ispossible to significantly increase the solubility of the drug substanceas well. Although there are a few marketed drugs that have beenformulated as solid dispersions, the major obstacle has been that theyare insufficiently stable, and in order to be able to apply thesedispersions widely in the pharmaceutical area significant stabilityimprovements are needed.

Forming a stable mixture of polymer matrix and drug, which maximizes thedissolution properties of the drug when exposed to aqueous medium (GIfluid) and which is preferably as uniform as possible is the aim whenpreparing solid dispersions.

Solid dispersion dosage forms may be formed by solvent method, by spraydrying, by spraying drug solution onto the carrier in a fluidized bedgranulator, by melt extrusion, by melt fusion, twin-screw extruder,evaporation, curing, microwaving, milling, ultra sound, spinning bymechanical admixture such as by ball milling and by mechanical admixtureat an elevated but non-melting temperature. See, for example, U.S. Pat.No. 4,880,585, U.S. Pat. No. 5,456,923, U.S. Pat. No. 6,254,889, U.S.Pat. No. 6,387,401, U.S. Pat. No. 6,706,283, U.S. Pat. No. 6,599,528,and U.S. Pat. No. 2004/0013697.

The solvent method for the preparation of solid dispersions ofpoorly-soluble drugs involves the dissolution of the matrix material ina solvent. The drug is either suspended or dissolved in thematrix—solvent mixture and the solvent is then removed to leave amixture of drug and matrix. Separation methods include precipitation,freeze-drying, vacuum drying or spray drying.

To dissolve the drug and the matrix in a common solvent is aconsiderable problem. If low drug concentrations and large amounts ofsolvent are used, the process of removing the solvent becomes expensiveand impractical. Surfactants like Tween and solubilzing agents likecyclodextrins have been used, however this can lead to low drug loadsand high concentrations of surfactants, which then change the propertiesof the matrix and which may be poorly-tolerated or even toxic. Suitablesolvents may only be found in those regarded by the FDA as toxic, whichrenders them impractical for pharmaceutical use.

Thus, despite many years of research and development and despite itstheoretical promise, solid dispersion approach has proved to be limitedin its practical application. Its problems include: (i) lack of ascientific framework and the need to use trial and error—only a specificmatrix developed for a specific drug; (ii) problems of scale up with themethods used; and (iii) problems with the physical and chemicalstability of the drug-polymer matrix. The problems with matrix selectionare due to the mutual incompatibility of the various requirements: lowhygroscopicity, fast dissolution, stability and easy to manufacture. Sofor instance, a polar matrix, which aids dissolution, when combined witha lipophilic drug, is inherently prone to phase separation, a tendencythat can be magnified if the polar matrix is also hygroscopic, whichreduces stability. On the other hand, a stable matrix requires lowmolecular mobility (to prevent phase changes of the drug), this usuallyrequires high molecular weight, which makes it difficult to find acommon solvent for drug and polymer. However, if the matrix is made froma less polar polymer, in order to more easily find a common solvent,then the dissolution rate is impaired. It would be highly desirable tofind the ideal matrix and a simple production process.

U.S. Pat. No. 5,145,684 discloses dispersible particles consistingessentially of a crystalline drug substance having a surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than about 400 nm anddispersions containing the particles exhibit unexpected bioavailability

WO 2004/069138 discloses a process for preparing a solid dispersionpharmaceutical product containing a pharmaceutical active ingredient anda polymer, wherein the pharmaceutical active ingredient is relativelyinsoluble and has a lower melting point or glass transition point thanthe water soluble polymer of choice, comprising first liquefying orsoftening the active ingredient and then adding the polymer to produce amixture of the liquefied or softened pharmaceutical active ingredientwith the polymer, then allowing said liquefied or softened mixture tobecome liquefied throughout, then allowing said mixture to form amolecular dispersion of pharmaceutical active ingredient and polymer,and then solidifying said dispersion in order to create a soliddispersion. Preferred polymers are polyvinylpyrrolidone (PVP) andhydroxypropylmethylcellulose (HPMC). Also hydrophobic polymers andmixtures of polymers can be used. The pharmaceutical active ingredientis preferably first melted and then mixed with a water-soluble polymer.

U.S. Pat. No. 6,337,092 discloses pharmaceutical compositions comprisingelectrostatic and steric-stabilized sub-micron and micron-size stablemicroparticles of water-insoluble or poorly soluble drugs, the particleshaving phospholipid coated surfaces and being stabilized with acombination of a highly purified charged phospholipid surface modifierand a block copolymer of ethylene oxide and propylene oxide.

US 2002/009494 discloses a composition comprising spray dried soliddispersions comprising a sparingly soluble drug andhydroxypropylmethylcellulose acetate succinate (HPMCAS) that provideincreased aqueous solubility and/or biavailability in a use environment.

US 2004/0052847 discloses a method of manufacturing an active agent oraldosage form, said method comprising the steps of: providing a singlephase working solution comprising an active agent, water, awater-soluble polymer and a solvent, said solvent selected from thegroup consisting of alcohol, acetone, and mixtures thereof; providingcore particles formed from a pharmaceutically acceptable material;combining said working solution with said particles to produce activeagent-coated particles; drying said active agent-coated particles; andforming said dried particles into an oral dosage form.

Numerous patents/patent applications deal with the preparation ofcompositions comprising fenofibrate, a lipophilic drug useful fortreating hyperlipidemia, particularly to reduce cholesterol andtriglyceride levels in patients at risk of cardiovascular disease. Thus,several compositions have been developed or proposed to improve thesolubility and bioavailability of fenofibrate and to reduce the foodeffect of blood levels of the active drug.

U.S. Pat. No. 4,961,890 discloses a process for preparing a controlledrelease formulation containing fenofibrate in an intermediate layer inthe form of crystalline microparticles included within pores of an inertmatrix. Sheu MT et al. (Int. J. Pharm. 103:137-146, 1994) reported thata dispersion of fenofibrate in polyvinylpyrrolydone (PVP) stillmaintains the same crystalline form of the drug itself. Palmieri GF etal. (Pharma Sciences 6:188-194, 1996) reported that a dispersion ofcrystalline fenofibrate could be prepared in PEG 4000.

U.S. Pat. No. 6,074,670, U.S. Pat. No. 6,277,405, U.S. Pat. No.6,589,522 and U.S. Pat. No. 6,652,881 (assigned to LaboratoiresFournier) disclose an immediate-release fenofibrate compositioncomprising an inert hydrosoluble carrier covered with at least one layercontaining a fenofibrate active ingredient in a micronized form having asize less than 20 μm, a hydrophilic polymer and a surfactant, andoptionally one or several outer phase(s) or layer(s).

U.S. Pat. No. 6,368,622 (assigned to Abbott Laboratories) discloses aprocess for preparing a solid formulation of a fibrate, particularlyfenofibrate, exhibiting more rapid dissolution, comprising forming amixture of the fibrate with a solid surfactant and granulating themixture by melting, mixing, and congealing, then optionally forming afinished dosage form. U.S. Pat. No. 6,465,011 (Abbott Laboratories)discloses a composition comprising a fibrate, particularly fenofibrate,dissolved in a hydrophilic, amorphous polymer carrier in which saidfibrate is present as a metastable, amorphous phase. WO 00/72829 (AbbottLaboratories) discloses a composition for lipid-regulating drugsincluding fenofibrate comprising the active drug and excipient in aeutectic mixture.

U.S. Pat. No. 7,037,529 and U.S. Pat. No. 7,041,319 (assigned toLaboratoires Fournier) disclose fenofibrate compositions comprisinggranulates, wherein the granulates comprise inert carrier particlescoated with an admixture comprising at least one hydrophilic polymer,micronized fenofibrate and optionally a surfactant and wherein thecomposition has a high dissolution rate in solutions of surfactants.

US 2006/0222707, assigned to Teva Pharmaceuticals, discloses apharmaceutical composition comprising a fibrate drug, particularlyfenofibrate, in intimate association with a surfactant mixturecomprising PEG 6000 and Poloxamer 407. The composition is prepared by aprocess comprising: (a) providing melted menthol; (b) mixing meltedmenthol with the fibrate drug and a surfactant mixture comprising PEG6000 and Poloxamer 407 to dissolve at least part of the fibrate drug andthe surfactant mixture, and removing the menthol via sublimation.

WO 2006/060817 (Abbott Laboratories) discloses an oral pharmaceuticalcomposition comprising fenofibrate and at least one pharmaceuticallyacceptable polymer and, optionally, at least one pharmaceuticallyacceptable surfactant. The composition can be in the form of a soliddispersion that forms a suspension upon in contact with an aqueousmedium. The suspension comprises crystalline and/or amorphousfenofibrate particles of various particle sizes. The solid dispersionsare prepared by a melt-extrusion method.

US 2003/0224058 (now U.S. Pat. No. 7,276,249), US 2004/0058009, US2004/0087656 and US 2005/0276974, US 2006/0110444, US 2006/0222707 andWO 2004/041250, (assigned to Elan Pharma and Fournier Laboratories)disclose nanoparticulate compositions comprising a fibrate, preferablyfenofibrate, and at least one surface stabilizer adsorbed on the surfaceof the fibrate particles. The fenofibrate particles have an effectiveaverage particle size of less than about 2000 nm and are obtained bymilling, homogenization or precipitation techniques and then coating bythe surface stabilizers to prevent aggregation. The formulationscontaining fenofibrate as either a nanoparticulate or a moleculardispersion in a solid dosage form eliminate the food effect associatedwith fenofibrate.

Some more recent publications disclose methods and compositionscomprising low-solubility drugs and two polymers.

US 2003/0104063 discloses a pharmaceutical composition comprising: (a) asolid dispersion comprising a low-solubility drug and a matrix (whichcan be formed by one or more polymers), wherein at least a major portionof said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer which further improves solubility in theuse environment and may not be part of the drug/matrix dispersion,instead it is mixed in with the drug/matrix particles or givenseparately.

US 2003/0228358 discloses a pharmaceutical composition comprising asolid amorphous dispersion of a low-solubility drug and aconcentration-enhancing polymer, administered together with a lipophilicmicrophase-forming material, which may be present as part of the solidamorphous dispersion or mixed in with the dispersion or even givenseparately with the dispersion.

US 2007/0141143 discloses a solid composition comprising a plurality ofparticles, said particles comprising a low-solubility drug and apoloxamer, at least a substantial portion of said drug in said particlesbeing amorphous and being in intimate contact with said poloxamer insaid particles, and further optionally comprising aconcentration-enhancing polymer.

US 2007/0148232 discloses solid compositions with improved physicalstability comprising an amorphous, low-solubility drug, a poloxamer, anda stabilizing polymer, preferably a cellulosic polymer. The compositionsare prepared by a solvent-based process and spray-drying and providegood physical stability during storage and concentration enhancement ofdissolved drug when administered to an aqueous environment.

Statins are currently among the most therapeutically effective drugsavailable for reducing the level of LDL in the blood stream of a patientat risk for cardiovascular disease. Statins are also known to raise HDLcholesterol levels and decrease total triglyceride levels. The mainstatins currently used in therapeutics are: pravastatin, simvastatin,lovastatin, fluvastatin, atorvastatin and rosuvastatin.

US 2001/0006662 discloses a composition comprising a lipid-regulatingagent, e.g. atorvastatin or pravastatin, dissolved or dispersed in ahydrophilic, amorphous polymer in which said lipid-regulating agent ispresent as a meta-stable, amorphous phase. WO 03/103640 describes ananoparticulate composition (effective average particle size less thanabout 2000 nm) comprising statin such as lovastatin or simvastatinincluding surface stabilizer or combinations of statin and othercholesterol lowering agents. US 2002/0034546 discloses a pharmaceuticalcomposition which is useful for cholesterol lowering and reduction ofthe risk of myocardial infarction, which includes a statin, such aspravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin orfluvastatin, in combination with aspirin, in a manner to minimizeinteraction of aspirin with the statin and to minimize side effects ofaspirin.

Compositions comprising fenofibrate and a statin have been described. US2005/0096391 discloses a particulate material comprising fenofibrate androsuvastatin in a hydrophobic, a hydrophilic or a water-misciblevehicle. US 2006/0068015 and US 2007/0009603 discloses pharmaceuticalcompositions in particulate form or in solid dosage forms comprising acombination of fenofibrate and atorvastatin, which are manufacturedwithout any need of addition of water or aqueous medium and comprise atleast 80% of the active substances fenofibrate and atorvastatin indissolved form, or, optionally, atorvastatin in micronized form, inorder to ensure suitable bioavailability.

Compositions comprising tacrolimus, an immunosuppressive lipophilic drugused mainly after allogenic organ transplant to prevent organ rejection,have been described. US 2006/0159766 is directed to nanoparticulatetacrolimus compositions comprising tacrolimus particles having aneffective average particle size of less than about 2000 mn and at leastone surface stabilizer. US 2006/0287352 discloses a modified releasecomposition comprising tacrolimus that may be coated with an entericcoating and/or may comprise a solid dispersion or a solid solution oftacrolimus in a hydrophilic or water-miscible vehicle and one or moremodifying release agents; and/or may comprise a solid dispersion or asolid solution of tacrolimus in an amphiphilic or hydrophobic vehicleand optionally one or more modifying release agents. U.S. Pat. No.6,884,433 describes sustained-release formulation comprising a soliddispersion composition, wherein the solid dispersion compositioncomprises tacrolimus or its hydrate, in a mixture comprising awater-soluble polymer and a water-insoluble polymer, and an excipient.

US 2004/0198645 discloses a solid pharmaceutical composition comprisinga poorly water-soluble drug (e.g. cyclosporin A), a polymer which issolid at room temperature, and a surfactant which is solid at roomtemperature and which has a HLB value of between 8 and 17.

U.S. Pat. No. 7,101,576 discloses a megestrol acetate formulationcomprising megestrol particles having an effective average particle sizeof less than about 2000 nm, and at least one surface stabilizer (e.g.,polymer) associated with the surface of the particles.

US 20060062809 describes solid dispersions comprising a poorly solublebioactive compound (e.g. itraconazole) dispersed and characterized in apolymer matrix which may comprise more than one polymer. US 2005/0191359of the present applicant discloses a hydrophilic dispersion ofnano-sized particles comprising an active compound selected from amacrolide antibiotic, donepezil hydrochloride, an azole compound (e.g.itraconazole) and a taxane; and an amphiphilic polymer which wraps saidactive compound in a non-crystalline manner to form a nano-sizedmolecular entity in which no valent bonds are formed.

U.S. Pat. No. 6,221,399 describes a method of making a solidinterpolymer complex for use as a controlled release matrix for acontrolled release product for oral administration, from a first polymerand one or more second complementary polymers capable of complexing withthe first polymer to form the interpolymer complex, wherein one of thefirst polymer or the second complementary polymer is a syntheticpolymer, including the steps of: (i) dissolving the first polymer in asolvent; (ii) dissolving the second complementary polymer in a solventtherefor, the solvent for said second polymer being the same as thatused for step (i) or different; (iii) the solvent in at least one ofstep (i) or (ii) functioning as a complexation inhibitor or adding acomplexation inhibitor to the solution of step (i) or the solution ofstep (ii), so that a complexation inhibitor is present to prevent theinterpolymer complex from precipitating from solution prior to step(vi); (iv) mixing together the solutions of steps (i) and (ii); (v) ifnecessary, adjusting the pH of the mixture of step (iv) to insure thedesired complexation when solvent is removed while avoidingprecipitation of the complex; and (vi) spraying the resulting solutioninto a vessel to remove solvent, including any complexation inhibitoradded thereto, to enable the polymers to complex and thereby producesolid particles of said complex.

US 2006/0062809 describes solid dispersions comprising a poorly solublebioactive compound dispersed in a polymer matrix comprising more thanone polymer, characterized in that a first polymer allows a homogenousor molecular dispersion of the bioactive compound in the polymer matrix,while a second polymer has a dissolution profile associated with thecreation of a micro-environment enhancing the dissolution of thebioactive compound in an aqueous environment.

US 2007/0026062 describes a solid dosage form comprising a soliddispersion or solid solution of a fibrate selected from gemfibrozil,fenofibrate, bezafibrate, clofibrate, ciprofibrate and activemetabolites and analogues thereof including any relevant fibric acidsuch as fenofibric acid in a vehicle, which is hydrophobic, hydrophilicor water-miscible, wherein the therapeutic effect of the solid dosageform in a patient is essentially independent of whether the solid dosageform is administered to the patient in fed or fasted state.

Although numerous patents/patent applications propose different methodsfor the preparation of formulations of lipophilic agents, there is stilla need for such formulations exhibiting immediate release and improvedbioavailability and for methods for their preparation that are moreefficient and less complex than the available methods.

SUMMARY OF THE INVENTION

The present invention provides a solid composition comprising at leastone lipophilic active compound, in which the at least one lipophilicactive compound has modified physico-chemical properties in comparisonto the same at least one lipophilic active compound used as the startingproduct for preparation of the composition. This composition is stableand upon contact with aqueous media forms a colloidal nanodispersion.

In the composition of the invention, the at least one lipophilic activecompound interacts and is interwoven with a polymeric entity/matrixformed by two or more polymers (herein in the specification designated“polymer matrix” or “polymeric entity”) possessing ahydrophobic-hydrophilic range. This polymeric matrix is not crosslinkedand no covalent interaction occurs between the two or more polymers thatform the polymeric matrix and between the two or more polymers and theat least one lipophilic active compound.

The interaction between the lipophilic active compound and the two ormore polymers gives rise to self-assembly of a complex, hereindesignated “polymers-lipophilic active compound complex”, in which thelipophilic active compound is fixated within the polymermatrix/polymeric entity that surrounds it, but is not linked to thepolymers by any covalent bond. In the polymers-lipophilic activecompound complex, the lipophilic active compound possesses modifiedphysico-chemical properties, more specifically modified thermalproperties, which are characterized by either decreased enthalpy ofmelting or both decreased enthalpy of melting and decreased temperatureof melting, as compared to the bulk active compound, e.g., crystallineactive compound, used for the preparation of the composition.

Thus, the present invention relates to a solid composition that forms acolloidal nanodispersion upon contact with aqueous media, saidcomposition comprising at least one lipophilic active compound and twoor more polymers, in which composition the at least one lipophilicactive compound is interwoven with a polymeric matrix formed by the twoor more polymers, wherein at least one of the two or more polymers is anamphiphilic polymer and at least another of the two or more polymers iseither a hydrophilic polymer or an amphiphilic polymer with ahydrophobic-hydrophilic balance different from the first amphiphilicpolymer, and each of the at least one lipophilic active compounds hasmodified physico-chemical properties as compared to the same lipophilicactive compound used as the starting product for the preparation of thecomposition.

In one embodiment, the at least one lipophilic active compound in thecomposition has modified thermal properties, characterized by decreasedenthalpy of melting (ΔH_(melt)) as compared to the bulk active compound,e.g., crystalline active compound, used for the preparation of thecomposition. In another embodiment, the modified thermal properties arecarachterized by both decreased enthalpy of melting (ΔH_(melt)) anddecreased temperature of melting (T_(melt)), as compared to the bulkactive compound, e.g., crystalline active compound, used for thepreparation of the composition.

The interaction between the lipophilic active compound and the two ormore polymers results in creation of a hydrophobic-hydrophilic gradientor range that enables formation of a colloidal nanodispersion uponcontact of the composition with aqueous media, facilitating fast releaseof the lipophilic active compound and ensuring its high bioavailability.The amphiphilic polymer is the gradient inducer, namely, it forms the“bridge” between the hydrophobic and the hydrophilic segments in thelipophilic drug-polymers complex and induces the formation of thehydrophobic-hydrophilic gradient.

The lipophilic active compound may be a lipophilic drug, both for humanand veterinary use, or a nutraceutical. In one preferred embodiment, theactive compound is a lipophilic drug and the composition of theinvention is a pharmaceutical composition, preferably for oraladministration. In another embodiment, the lipophilic compound is aveterinary drug, and the composition is a veterinary composition. In afurther embodiment, the lipophilic compound is a nutraceutical and thecomposition is a nutraceutical composition.

In one preferred embodiment, two polymers, one of which must be anamphiphilic polymer, form the polymeric entity. In one embodiment, afirst polymer is an amphiphilic polymer and the second polymer is anamphiphilic polymer with different hydrophobic-hydrophilic balance, forexample with a higher degree of hydrophilicity than the first one. Inanother more preferred embodiment, the first polymer is an amphiphilicpolymer and the second polymer is a hydrophilic polymer.

In another preferred embodiment, three polymers, one of which must be anamphiphilic polymer, form the polymeric entity. In one embodiment, thethree polymers are amphiphilic polymers with differenthydrophobic-hydrophilic balance. In a more preferred embodiment, two ofthe polymers are amphiphilic polymers of different hydrophilicities andthe third polymer is a hydrophilic polymer.

The present invention further relates to a method for the preparation ofa composition of the invention comprising the steps:

(i) preparing a clear and homogeneous solution of the two or morepolymers and the at least one lipophilic active compound in a mixture ofwater and organic solvent; and

(ii) drying the polymers-lipophilic active compound complex clearsolution of (i) to form a dry powder.

The dry powder composition obtained by the method of the inventioncontains the at least one lipophilic active compound fixated within thepolymeric entity possessing a hydrophilic-hydrophobic gradient. The thusfixated lipophilic active compound is characterized by decreasedenthalpy of melting or by decrease of both enthalpy of melting andtemperature of melting of the lipophilic active compound as comparedwith the bulk lipophilic active compound used as the starting productfor preparation of the composition. Upon contact with water or withaqueous media, e.g., biological fluids, the powder composition isconverted into a colloidal dispersion with particles size in thenanoscale range.

The compositions of the invention are stable for at least 12 months whenstored at 25° C. and 60% RH. The stored compositions do not exhibit anychanges in their chemical or physicochemical properties such asformation of colloidal nanodispersion upon contact with aqueous mediaand decreased enthalpy of melting and decreased temperature of meltingas the initial composition.

Another advantage of the compositions of the invention is thepossibility of designing the composition such that a lipophilic drugwill be released either in the gut or in the intestine. Thus, when thelipophilic active compound is a lipophilic drug, the polymers can beselected such that the drug release may be pH dependent so that thelipophilic drug will be released either in the gut or in the intestine.Thus, in a more preferred embodiment of the invention, the lipophilicdrug powder forms colloidal nanodispersion upon contact with aqueousmedia or biological fluids with pH 6-8 that corresponds to the pH ofintestinal fluids.

The present invention also relates to pharmaceutical compositionscomprising at least one lipophilic drug interwoven with, and fixatedwithin, the polymeric entity having a hydrophobic-hydrophilic gradientand may further comprise one or more pharmaceutically acceptablecarriers and/or excipients, preferably solid carriers and/or excipients.The composition can be further processed and formulated into dosageforms for oral administration such as, but not limited to, capsules,tablets, beads, grains, pills, granulates, granules, powder, pellets,sachets, troches, oral suspensions and aerosol. In one more preferredembodiment, the pharmaceutical composition of the invention isformulated into tablets.

The pharmaceutical composition of the invention may comprise a solelipophilic drug or a combination of more than one, preferably two,drugs, in which one of the drugs is lipophilic and the other may belipophilic or not.

The tablets of the invention disintegrate in aqueous media or biologicalfluids with formation of colloidal nanodispersion comprising thelipophilic drug. These nanodispersions are reversible: they can be driedand redispersed or diluted while keeping the same properties of thelipophilic drug.

The collective properties of the lipophilic drug composition of theinvention including the thermal behavior, release, bioavailability,dispersability and dissolution are stable and reproducible.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the Differential Scanning Calorimetry (DSC) thermogram ofspray-dried fenofibrate alone (Example 1) as shown in Table 3 (Example11).

FIG. 2 depicts the Differential Scanning Calorimetry (DSC) thermogram ofthe fenofibrate composition according to the invention comprisingCopovidone K28 and NaCMC (Example 8) as shown in Table 3 (Example 11).

FIG. 3 depicts the Differential Scanning Calorimetry (DSC) thermogram ofthe fenofibrate composition according to the invention comprisingPoloxamer 407 and NaCMC (Example 4.2) as shown in Table 3 (Example 11).

FIG. 4 depicts the pharmacokinetic profile of albendazole formulation,Example 30, vs. a commercial albendazole product (Albazen).

FIG. 5 depicts the comparative dissolution rate of resveratrol rawpowder vs. the resveratrol formulations comprising Poloxamer 407 andNaCMC or Poloxamer 407 and sodium alginate (Examples 34-35) in the modelfasted duodenal solution

DETAILED DESCRIPTION OF THE INVENTION

As described in the Background of the Invention section hereinbefore,the Applicant of the present application, Solubest Ltd., has developed abasic technology described in U.S. Pat. No. 6,878,693 and U.S. Pat. No.7,081,450 for the solubilization and improved bioavailability oflipophilic and hydrophilic active compounds in the form of nano-sizedparticles, wherein said active compound is surrounded by and entrappedwithin an amphiphilic polymer, to form a water-soluble nano-sized entityin which non-valent bonds are formed between said active compound andsaid amphiphilic polymer such that said bonds fixate said activecompound within said polymer, in which nano-sized entity the activecompound is in the amorphous or partially crystalline state and whereinsaid amphiphilic polymer does not form rigid matrices nor cross-linkedpolymers.

Contrary to the former concept, in accordance with the present inventionthe lipophilic active compound is interwoven with a polymeric entityformed by two or more polymers instead of a sole polymer, thus forming apolymers-lipophilic active compound complex system with ahydrophobic-hydrophilic gradient that enables formation of colloidalnanodispersion upon contact with aqueous media.

As used herein in the specification, the terms “polymeric matrix” or“polymeric entity”, used interchangeably, refer to a non-crosslinkedmatrix or entity formed by the two or more polymers in which no covalentbonds exist between the two or more polymers.

The terms “polymers-lipophilic active compound complex” or “lipophilicactive compound-polymers complex”, used herein interchangeably, refer toa complex formed by the two or more polymers and the at least one activecompound by self-assembly, wherein the at least one active compound iswrapped within/interwoven with, and is fixated within, the polymericentity formed by the two or more polymers, but is not linked to thepolymers by any covalent bond, and exhibits modified physico-chemicalchemical properties as compared to the starting bulk active compoundused for preparation of the composition. The two or more polymers andthe at least one active compound are linked by non-covalent bonds thatinclude electrostatic forces, Van der Waals forces and hydrogen bonds.The polymeric entity is not crosslinked and does not form rigidmatrices. It should be noted that, unlike cyclodextrins or inclusioncomplexes or other “encapsulants”, the complex of the present inventiondoes not provide a ready-made cavity or any cavity at all, but ratherthe polymer carriers are “interwoven” with the active compound creatinga hydrophobic-hydrophilic gradient, all this accomplished by a selfassembly mechanism.

The terms “interwoven with” is used herein to denote the condition inwhich the lipophilic drug is positioned in intimate contact within thepolymeric entity.

Thus, in a first aspect, the present invention provides a composition inwhich at least one liphophilic active compound is interwoven with apolymeric entity formed by two or more polymers, wherein at least one ofthe two or more polymers is an amphiphilic polymer and at least anotherof the two or more polymers is an amphiphilic polymer with a differenthydrophobic-hydrophilic balance or a hydrophilic polymer, and theinteraction between the lipophilic active compound and the two or morepolymers results in modification of its physico-chemical properties andenables formation of a colloidal nanodispersion comprising theliphophilic active compound upon contact with aqueous media.

The term “nanodispersion” is used herein to denote a dispersion in whichat least 70% of the particles have a size less than 2000 nm, preferablyless than 1500 nm, more preferably less than 1000 nm.

As used herein, the term “hydrophobic-hydrophilic balance” of theamphiphilic polymer refers to the “balance of hydrophobic andhydrophilic segments in the amphiphilic polymer chain” and both termsmay be used herein interchangeably.

The lipophilic active compounds that can be used in accordance with thepresent invention include biologically active compounds and imagingagents and, in particular, drugs for human and veterinary medicine, andnutraceutical or dietary supplements. They include liphophilicwater-insoluble compounds having solubility less than 10 mg/ml,preferably less than about 1 mg/ml and even less than about 0.1 mg/ml.

Suitable lipophilic active substances according to the inventioninclude, but are not limited to, lipophilic active compounds or a salt,isomer, ester, ether or other derivative thereof selected fromacetylcholinesterase inhibitors, analgesics and nonsteroidalantiinflammatory agents, anthelminthics, antiacne agents, antianginalagents, antiarrhythmic agents, anti-asthma agents, antibacterial agents,anti-benign prostate hypertrophy agents, anticancer agents andimmunosuppressants, anticoagulants, antidepressants, antidiabetics,antiemetics, antiepileptics, antifungal agents, antigout agents,antihypertensive agents, antiinflammatory agents, antimalarials,antimigraine agents, antimuscarinic agents, antineoplastic agents,antiobesity agents, antiosteoporosis agents, antiparkinsonian agents,antiproliferative, antiprotozoal agents, antithyroid agents, antitussiveagent, anti-urinary incontinence agents, antiviral agents, anxiolyticagents, appetite suppressants, beta-blockers, cardiac inotropic agents,chemotherapeutic drugs, cognition enhancers, contraceptives,corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunctionimprovement agents, expectorants, gastrointestinal agents, histaminereceptor antagonists, hypnotics, immunosuppressants, keratolytics, lipidregulating agents, leukotriene inhibitors, macrolides, muscle relaxants,neuroleptics, nutritional agents, opiod analgesics, protease inhibitors,sedatives, sex hormones, stimulants, vasodilators, essential fattyacids, non-essential fatty acids, proteins, peptides, sugars, vitamins,nutraceuticals, natural agents, or mixtures thereof.

A description of these classes of compounds and a listing of the specieswithin each class may be found in Remingtons's The Science and Practiceof Pharmacy, 20th Ed (2000). All these drug substances are commerciallyavailable and/or can be prepared by techniques known in the art.

Among the lipophilic active compounds for use in the invention arelipophilic drugs of the Biopharmaceutical Classification System (BCS)class II drugs, characterized by low solubility and high permeability,and class IV drugs, characterized by low solubility and lowpermeability.

Representative examples of lipophilic substances that can be used inaccordance with the present invention include, but are not limited to,lipophilic active compounds or a salt, isomer, ester, ether or otherderivative thereof selected from:

(i) acetylcholinesterase inhibitors selected from donepezil, tacrine,pyridostigmine;

(ii) analgesics and nonsteroidal antiinflammatory agents (NSAIA)selected from aloxiprin, auranofin, azapropazone, benorylate, capsaicin,celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofencalcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen,oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib,sulindac, tetrahydrocannabinol, tramadol and tromethamine,

(iii) anthelminthics selected from albendazole, bepheniumhydroxynaphthoate, cambendazole, dichlorophen, fenbendazole, ivermectin,mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel,pyrantel embonate and thiabendazole;

(iv) antiacne agents such as isotretinoin and tretinoin;

(iv) antianginal agents selected from amyl nitrate, glyceryl trinitrate(nitroglycerin), isosorbide dinitrate, isosorbide mononitrate,pentaerythritol tetranitrate, and ubidecarenone (coenzyme Q10);

(v) antiarrhythmic agents selected from amiodarone HCl, digoxin,disopyramide, flecainide acetate and quinidine sulfate;

(vi) anti-asthma agents selected from zileuton, zafirlukast, terbutalinesulfate, montelukast, and albuterol;

(vii) antibacterial agents, including antibiotics, selected fromalatrofloxacin, azithromycin, aztreonum, baclofen, benzathinepenicillin, cefixime, cefuraxime axetil, cinoxacin, ciprofloxacin HCl,clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin,doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin,imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid,nitrofurantoin, norfloxacin, ofloxacin, phenoxymethyl penicillin,rifabutine, rifampicin, rifapentine, sparfloxacin, spiramycin,sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide,sulphadiazine, sulphafurazole, sulpha-methoxazole, sulphapyridine,tetracycline, trimethoprim, trovafloxacin, and vancomycin;

(vii)anti-benign prostate hypertrophy (BPH) agents selected fromalfuzosin, doxazosin, phenoxybenzamine, prazosin, terazosin andtamulosin;

(viii) anticancer agents and immunosuppressants selected from abarelix,aldesleukin, alemtuzumab, alitretinoin, all-trans retinoic acid (ATRA),altretamine, amifostine, aminoglutethimide, amsacrine, anastrozole,arsenic trioxide, asparaginase, azacitidine, azathioprine, BCG Live,bevacuzimab (avastin), bexarotene, bicalutamide, bisantrene, bleomycin,bortezomib, busulfan, calusterone, camptothecin, capecitabine,carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, cyclophosphamide, cyclosporin, cytarabine,dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin,dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin HCl,dromostanolone propionate, ellipticine, enlimomab, estramustine,epirubicin, epoetin alfa, erlotinib, estramustine, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, mofetil mycophenolate,nandrolone, nelarabine, nilutamide, nofetumomab, oprelvekin,oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine,rasburicase, rituximab, sargramostim, sirolimus, sorafenib,streptozocin, sunitinib maleate, tacrolimus, tamoxifen citrate,temozolomide, teniposide, testolactone, thioguanine, thiotepa,topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracilmustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate,and zoledronic acid;

(ix) anticoagulants selected from cilostazol, clopidogrel, dicumarol,dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, andtirofiban;

(x) antidepressants selected from amoxapine, bupropion, citalopram,clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl,nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl,trimipramine maleate, and venlafaxine HCl;

(xi) antidiabetics selected from acetohexamide, chlorpropamide,glibenclamide, gliclazide, glipizide, glimepiride, glyburide, miglitol,pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide andtroglitazone;

(xii) antiepileptics selected from beclamide, carbamazepine, clonazepam,thotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin,methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,phenacemide, phenol barbitone, phenytoin, phensuximide, primidone,sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;

(xiii) antifungal agents selected from amphotericin, butenafine HCl,butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole,natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl,terconazole, tioconazole and undecenoic acid;

(xiv) antigout agents selected from allopurinol, probenecid andsulphinpyrazone;

(xv) antihypertensive agents selected from amlodipine, benidipine,benezepril, candesartan, captopril, darodipine, dilitazem HCl,diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate,felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan,isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine,nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril,reserpine, terazosin HCl, telmisartan, and valsartan;

(xvi) antimalarial agents selected from amodiaquine, chloroquine,chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl,pyrimethamine and quinine sulfate;

(xvii) antimigraine agents selected from dihydroergotamine mesylate,ergotamine tartrate, frovatriptan, methysergide maleate, naratriptanHCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, andzolmitriptan;

(xviii) antimuscarinic agents selected from atropine, benzhexol HCl,biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,oxyphencyclimine HCl and tropicamide

(xix) antiparkinsonian agents selected from bromocriptine mesylate,lysuride maleate, pramipexole, ropinirole HCl, and tolcapone;

(xx) antiprotozoal agents selected from atovaquone, benznidazole,clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate,dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone,ornidazole and tinidazole;

(xxi) antithyroid agents selected from carbimazole and propylthiouracil;

(xxii) antitussive agent such as benzonatate;

(xxiii) antiviral agents selected from abacavir, amprenavir,delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine,ritonavir, saquinavir, and stavudine;

(xxiv) anxiolytics, sedatives, hypnotics and neuroleptics selected fromalprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide,chlormethiazole, chlorpromazine, chlorprothixene, clonazepam, clobazam,clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone,flunitrazepam, triflupromazine, flupenthixol decanoate, fluphenthixoldecanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam,medazepam, meprobamate, mesoridazine, methaqualone, methylphenidate,midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone,perphenazine pimozide, prochlorperazine, propofol, pseudoephedrine,quetiapine, risperidone, sertindole, sulpiride, temazepam, thioridazine,triazolam, zolpidem, and zopiclone;

(xxv) beta.-blockers selected from acebutolol, alprenolol, atenolol,labetalol, metoprolol, nadolol, oxprenolol, pindolol and propranolol;

(xxvi) cardiac inotropic agents selected from anrinone, digitoxin,digoxin, enoximone, lanatoside C and medigoxin;

(xxvii) corticosteroids selected from beclomethasone, betamethasone,budesonide, cortisone acetate, desoxymethasone, dexamethasone,fludrocortisone acetate, flunisolide, fluocortolone, fluticasonepropionate, hydrocortisone, methylprednisolone, prednisolone, prednisoneand triamcinolone;

(xxviii) diuretics selected from acetazolamide, amiloride,bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone,ethacrynic acid, frusemide, metolazone, spironolactone and triamterene;

(xxix) gastrointestinal agents selected from bisacodyl, cimetidine,cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole,loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl,pantoprazole, rabeprazole sodium, ranitidine HCl and sulphasalazine;

(xxx) histamine H₁- and H₂-receptor antagonists selected fromacrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine,clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine,dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizineHCl, oxatomide, and terfenadine;

(xxxi) keratolytic agents selected from acetretin, calciprotriene,calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate,retinoids, targretin, and tazarotene;

(xxxii) lipid regulating/hypolipidemic agents selected fromatorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate,fenofibrate, fluvastatin, gemfibrozil, hesperetin, lovastatin,pravastatin, probucol, and simvastatin;

(xxxiv) muscle relaxants selected from cyclobenzaprine, dantrolenesodium and tizanidine HCl;

(xxxv) opioid analgesics selected from codeine, dextropropoxyphene,diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine,nalbuphine and pentazocine;

(xxxvi) sex hormones selected from clomiphene citrate, cortisoneacetate, danazol, dehydroepiandrosterone, ethynyl estradiol,finasteride, fludrocortisone, fluoxymesterone, medroxyprogesteroneacetate, megestrol acetate, mestranol, methyltestosterone, mifepristone,norethisterone, norgestrel, oestradiol, conjugated estrogens,progesterone, rimexolone, stanozolol, stilbestrol, testosterone andtibolone;

(xxxvii) stimulants selected from amphetamine, dexamphetamine,dexfenfluramine, fenfluramine and mazindol;

(xxxviii) nutraceutical agents selected from calcitriol, carotenes,chrysin, dihydrotachysterol, flavonoids, hesperitin, jasmonates, lipoicacid, lutein, lycopene, essential fatty acids, non-essential fattyacids, naringenin, phytonadiol, quercetin, vitamins including vitamin A,vitamin B₂, vitamin D and derivatives, vitamin E, and vitamin K,coenzyme Q10 (ubiquinone), plant extracts, and minerals.

Preferred lipophilic active compounds used in the present invention arethe drugs fenofibrate, atorvastatin, clarithromycin, itraconazole,nifedipine, albendazole, and tacrolimus; the veterinary drugsalbendazole, itraconazole and fenbendazole; and the nutraceuticalshesperetin and resveratrol.

As defined according to the invention, at least one of the two or morepolymers entrapping the lipophilic active compound must be anamphiphilic polymer and at least one of the other two or more polymersmay be an amphiphilic polymer of a different hydrophobic-hydrophilicbalance or a hydrophilic polymer, thus creating a broadhydrophobic-hydrophilic range.

Examples of amphiphilic polymers suitable for use in the inventioninclude, but are not limited to, polyethylene oxides (PEO) (alsocommonly referred to as polyethylene glycol or PEG), PEO derivatives,PEO copolymers such as PEO/polypropylene glycol (PPG) copolymers,PEG-modified starches, poloxamers, poloxamines, polyvinylpyrrolidones(PVP), hydroxypropyl cellulose, hypromellose and esters thereof, vinylacetate/vinylpyrrolidone random copolymers, polyacrylates and copolymersthereof, polymethacrylates and copolymers thereof, polyacrylic acidcopolymers, polymethacrylic acid copolymers, plant proteins and plantprotein hydrolysates.

In one embodiment, the amphiphilic polymer is polyethylene glycol (PEG)or polyethylene oxide (PEO) or a derivative thereof. PEG/PEO refers toan oligomer or polymer of ethylene oxide with different molecularweights. Derivatives of PEG/PEO include ethers, preferably C₁-C₁₄ alkylethers, more preferably the methyl ether (mPEG).

In a preferred embodiment of the invention, the amphiphilic polymer is ablock copolymer. In a more preferred embodiment, the block copolymer isa poloxamer. Poloxamers are block copolymers of PEG and PPG, composed ofa central hydrophobic block of polypropylene glycol (PPG) flanked by twohydrophilic blocks of polyethylene glycol (PEG). The lengths of thepolymer blocks can be customized and thus many different poloxamersexist that have slightly different properties such as poloxamer 188, 335and 407. In one preferred embodiment of the invention, the amphiphilicpolymer is Poloxamer 407, also known by the BASF trade name LutrolF-127, which has approximately 101 repeat units of the two PEG blocksand approximately 56 repeat units of the propylene gycol block.Poloxamines are tetrafunctional block copolymers consisting of fourPEG/PPG blocks centered on an ethylenediamine moiety.

In another embodiment, the amphiphilic polymer is a polyvinylpyrrolidone(PVP) or a copolymer thereof, particularly Copovidone, a4-vinylpyrrolidone-vinyl acetate copolymer.

Hypromellose stands for hydroxypropyl methylcellulose (HPMC) and estersthereof include hypromellose phthalate (HPMCP) and hypromellose acetatesuccinate (HPMCAS).

The protein hydrolysates useful as amphiphilic polymers according to theinvention can be a plant protein hydrolysate such as wheat, soy, rice,corn or flaxseed protein hydrolysate. Examples of proteins hydrolysatesinclude wheat gluten hydrolysate; examples of proteins useful asamphiphilic polymers include corn zein.

In preferred embodiments of the invention, the amphiphilic polymer is apoloxamer, more preferably Poloxamer 407, polyvinylpyrrolidone (PVP),Copovidone, a protein, a protein hydrolysate, or a combination thereof.

Examples of hydrophilic polymers suitable for use in the inventioninclude, but are not limited to, starch, sodium carboxymethylcellulose(NaCMC), hydroxyethylcellulose, polyvinyl alcohol, an alginate such assodium alginate, chitosan, and carrageenan.

In preferred embodiments of the invention, the hydrophilic polymer isNaCMC, sodium alginate or chitosan.

According to the present invention, amphiphilic and hydrophilic polymersas described above with different molecular weights can be used.Preferred for use in the invention are pharmaceutically acceptablepolymers, more preferably polymers approved for human use.

The composition according to the invention may comprise two or morepolymers, more preferably two or three polymers.

In one preferred embodiment, the composition of the invention comprisestwo polymers, wherein one is amphiphilic and the other is a hydrophilicpolymer. In preferred embodiments, the amphiphilic polymer is Poloxamer407 or Copovidone and the hydrophilic polymer is NaCMC, sodium alginateor chitosan.

In another preferred embodiment, both polymers in the composition of theinvention are amphiphilic polymers, for example, hypromellose and estersthereof, e.g. hypromellose acetate succinate, hypromellose phthalate,and protein hydrolysate, e.g., wheat gluten, or PVP and a plant protein,e.g., corn zein.

In a further preferred embodiment, the composition of the inventioncomprises three polymers. In one embodiment, one of the three polymersis an amphiphilic polymer and the other two are hydrophilic polymers. Inanother embodiment, the three polymers are amphiphilic polymers, eachhaving a different hydrophobic-hydrophilic balance. In a further morepreferred embodiment, two of the three polymers are amphiphilicpolymers, each having a different hydrophobic-hydrophilic balance, forexample Poloxamer 407 and PVP, or PVP and protein hydrolysate, e.g.wheat gluten, and the third polymer is a hydrophilic polymer, preferablyNaCMC.

In a more preferred embodiment, the at least one active compound is atleast one lipophilic drug and the composition of the invention is apharmaceutical composition comprising at least one lipophilic drugwrapped within a polymeric matrix formed by two or more polymers,wherein said polymeric matrix is not crosslinked and no covalentinteraction occurs between the two or more polymers and between thepolymers and the at least one lipophilic drug.

The pharmaceutical composition of the invention may comprise at leastone lipophilic drug selected from the group of lipophilic drugs recitedabove in the specification, preferably fenofibrate, atorvastatin,clarithromycin, itraconazole, nifedipine, albendazole, hesperetin ortacrolimus.

In one preferred embodiment, the pharmaceutical composition comprises asole lipophilic drug.

In one more preferred embodiment, the sole lipophilic drug isfenofibrate, a drug used to treat high cholesterol and high triglyceridelevels. In one embodiment, the pharmaceutical fenofibrate compositioncomprises fenofibrate and two polymers forming the polymeric matrix,wherein one of the polymers is an amphiphilic polymer, preferablyPoloxamer 407 and the other polymer is a hydrophilic polymer, preferablyNaCMC or sodium alginate.

In one embodiment, the invention provides a pharrmaceutical compositioncomprising about 5%-50%, preferably about 15%-35%, by weight offenofibrate, about 10%-60%, preferably about 25%-50%, by weight ofPoloxamer 407 and about 10%-60%, preferably about 25%-50%, by weight ofNaCMC or sodium alginate.

In another embodiment, the pharmaceutical fenofibrate composition of theinvention comprises fenofibrate and three polymers forming the polymericmatrix, wherein one of the three polymers is an amphiphilic polymer andthe other two polymers are hydrophilic polymers.

In a further embodiment, the pharmaceutical fenofibrate composition ofthe invention comprises fenofibrate and three polymers forming thepolymeric matrix, wherein two of the three polymers are amphiphilicpolymers with different hydrophobic-hydrophilic balance, for example,Poloxamer and PVP or PVP and a protein hydrolysate, e.g., wheat gluten,and and the third polymer is a hydrophilic polymer, preferably NACMC.

In another embodiment, the pharmaceutical composition of the inventioncomprises atorvastatin as the sole lipophilic drug. In one embodiment,the pharmaceutical atorvastatin composition comprises two polymersforming the polymeric matrix, wherein one of the polymers is anamphiphilic polymer, preferably Poloxamer 407, and the second polymer isa hydrophilic polymer, preferably NaCMC or sodium alginate. Thispharmaceutical composition preferably comprises about 5%-50% by weightof atorvastatin, about 10%-60% by weight of Poloxamer 407 and about10%-60% by weight of NaCMC or sodium alginate.

In another embodiment, the pharmaceutical composition of the inventioncomprises itraconazole as the sole lipophilic drug. In one embodiment,the pharmaceutical itraconazole composition comprises two polymersforming the polymeric matrix, wherein one of the polymers is anamphiphilic polymer, preferably Poloxamer 407, and the other polymer isa hydrophilic polymer, preferably NaCMC, sodium alginate or chitosan.

In one embodiment, the invention provides a pharmaceutical compositioncomprising about 5%-50% by weight of itraconazole, about 10%-60%,preferably about 25%-50%, by weight of Poloxamer 407 and about 10%-60%,preferably about 25%-50%, by weight of NaCMC or sodium alginate.

In another embodiment, the pharmaceutical composition of the inventioncomprises itraconazole and two amphiphilic polymers forming thepolymeric matrix, wherein the two amphiphilic polymers arepolyvinylpyrrolidone and a plant protein such as corn zein.

In other preferred embodiments, the pharmaceutical composition accordingto the invention comprises tacrolimus, nifedipine, clarithromycin, oralbendazole as the sole lipophilic drug and two polymers forming thepolymeric matrix, wherein one of the polymers is an amphiphilic polymer,preferably Poloxamer 407, and the other polymer is a hydrophilicpolymer, preferably NaCMC.

The pharmaceutical compositions of the present invention may comprisethe lipophilic drug and additional drugs, preferably one additionaldrug.

In one embodiment, the additional drug is a lipophilic drug present fromthe beginning in the feed solution used for the preparation of thecomposition (see description of the method of preparation hereinafter)and both lipophilic drugs are interwoven with the polymer matrix as aresult of self-assembling and each of them has modified physico-chemicalproperties as compared to the bulk lipophilic drug used as startingmaterial for preparation of the composition. In one preferredembodiment, such a composition comprises both fenofibrate andatorvastatin wrapped within a polymer matrix of Poloxamer 407 and NaCMC.

In another embodiment, the composition of the invention comprises thelipophilic drug interwoven with the polymeric matrix and another drugthat may be lipophilic or not and is not a part of the lipophilicdrug-polymer complex according to the invention and thus has notmodified physico-chemical properties. Such a composition is prepared byphysically mixing or formulating a solid composition of the inventionwith the additional drug. For example, the composition may be in theform of capsules containing granules of the solid composition of theinvention and granules containing the additional drug blended and filledto capsules or in the form of tablets such as bilayered tabletscomprising a layer of the solid composition of the invention and a layerof the additional drug. In one preferred embodiment, such a compositioncomprises fenofibrate interwoven with a polymer matrix of Poloxamer 407and NaCMC and aspirin formulated with lactose in the form of capsules orbilayered tablets.

The selection of the additional drug in the composition of the presentinvention comprising two drugs is made in accordance with thetherapeutic need. For example, for treatment of cardiovascular diseasesor disorders, suitable drugs for combined administration are lipidregulating agents, anticoagulants, antidiabetics and antihypertensivedrugs such as alpha- and/or beta-blockers, calcium channel blockers,angiotensin receptor blockers, and angiotensin converting enzyme (ACE)inhibitors. In the field of cancer therapy, suitable drugs for combinedadministration include, but are not limited to, two anticancer agentshaving different mechanisms of action or an anticancer agent with aP-glycoprotein (P-gp) inhibitor known to limit rapid elimination and toincrease the bioavailability of the anticancer agent.

In one embodiment, the pharmaceutical composition of the presentinvention comprises a combination of two or more drugs of the samepharmaceutical category, such as two or more lipid regulating agents.Specifically, suitable drugs for combined administration in this caseare fenofibrate and statins or HMG CoA reductase inhibitors useful tocontrol hypercholesterolemia. In one preferred embodiment, thepharmaceutical composition of the invention comprises a combination offenofibrate and atorvastatin.

In a further embodiment, the lipophilic active compound is a veterinarydrug and the invention provides a veterinary composition comprising atleast one lipophilic veterinary drug interwoven with a polymeric matrixformed by two or more polymers, wherein said polymeric matrix is notcrosslinked and no covalent interaction occurs between the two or morepolymers and between the polymers and the at least one lipophilicveterinary drug. In one embodiment, the veterinary composition comprisesitraconazole and a polymer matrix formed by an amphiphilic polymer,preferably Poloxamer 407, and a hydrophilic polymer, preferably chitosanor NaCMC, or the polymer matrix is formed by two amphiphilic polymers,preferably PVP and corn zein. In other embodiments, the veterinarycomposition comprises albendazole or fenbendazole and a polymer matrixformed by an amphiphilic polymer, preferably Poloxamer 407, and ahydrophilic polymer, preferably NaCMC,

In still a further embodiment, the lipophilic active compound is anutraceutical and the invention provides a nutraceutical compositioncomprising at least one lipophilic nutraceutical interwoven with apolymeric matrix formed by two or more polymers, wherein said polymericmatrix is not crosslinked and no covalent interaction occurs between thetwo or more polymers and between the polymers and the at least onelipophilic nutraceutical. In one preferred embodiment, the lipophilicnutraceutical, is resveratrol and two polymers form the polymericmatrix, wherein one of the polymers is an amphiphilic polymer,preferably Poloxamer 407, and the other is a hydrophilic polymer,preferably NaCMC, sodium alginate or chitosan. In another embodiment,the nutraceutical is hesperetin.

The nutraceutical composition of the invention may comprise othernutraceuticals or nutrients and dietary supplements.

In another aspect, the invention provides a method for the preparationof a composition of the invention, the method comprising the steps of:

(i) preparing a clear to opalescent and homogeneous solution of thepolymers and the at least one lipophilic drug in a mixture of water andorganic solvent, to form a polymers-lipophilic drug complex; and

(ii) drying the polymers-lipophilic drug complex clear solution of (i)to form the composition as a dry powder.

The polymers-lipophilic drug clear and homogeneous solution can beprepared in various ways according to the polymers used. The lipophilicdrug is always dissolved in an organic solvent that is miscible withwater and does not lead to precipitation of the polymers when theorganic solution containing the lipophilic drug is added to the polymersaqueous solution. Examples of such solvents include, but are not limitedto, acetic acid, acetonitrile, acetone, 1-butanol, 2-butanol,N,N-dimethylacetamide; N,N-dimethylformamide, dimethyl sulfoxide,1,4-dioxane, ethanol, formic acid, methanol, 3-methyl-1-butanol,methylethyl ketone, 2-methyl-1-propanol, 1-methyl-2-pyrrolidone,1-pentanol, n-propanol, 2-propanol and tetrahydrofuran. In preferredembodiments, the organic solvent is n-propanol, ethanol,1-vinyl-2-pyrrolidone or acetonitrile.

In one embodiment of the invention, the polymers-lipophilic drug clearand homogeneous solution is prepared by adding a solution of thelipophilic drug in an organic solvent to a homogeneous water solution ofthe polymers. The final solution consists of at least 50% by weight ofwater and less than 50% by weight of the organic solvent. Thehydrophilic polymer has to dissolve both in water and in the mixture oforganic solvent and water. This aqueous composition is crucial for thelipophilic drug-polymer complex formation. It should be noted that sucha procedure has not been described in the prior art and is unexpectedand non-obvious when dealing with solubilization of lipophilic actives.

The method above is suitable, for example, when one of the polymers isamphiphilic such as Poloxamer 407, and the other is hydrophilic such asNaCMC. As shown in the Examples hereinafter, fenofibrate was dissolvedin n-propanol and added to an aqueous solution of Poloxamer 407 andNaCMC (Example 4); atorvastatin was dissolved in 1-methyl-2-pyrrolidoneand added to an aqueous solution of Poloxamer 407 and NaCMC (Example19); atorvastatin and fenofibrate were dissolved in1-methyl-2-pyrrolidone and added to an aqueous solution of Poloxamer 407and NaCMC (Example 21); and itraconazole was dissolved in acetonitrileand added to an aqueous solution of Poloxamer 407 and NaCMC (Example24).

In another embodiment, the method comprises adding the amphiphilicpolymer and optionally water to the lipophilic drug organic solution,and then adding the lipophilic drug-amphiphilic polymer solution to anaqueous organic solvent solution of a hydrophilic polymer. The organicsolvent used for dissolving the hydrophilic polymer may be the same usedfor dissolving the lipophilic drug or may be a different solvent. In apreferred embodiment, it is the same solvent. Thus, in this way, thepolymers-atorvastatin composition of Example 20 was prepared bydissolving atorvastatin and Poloxamer 407 in n-propanol and adding thissolution to a solution of sodium alginate in aqueous n-propanol; and thepolymers-itraconazole composition of Example 23 was prepared bydissolving itraconazole and Poloxamer 407 in n-propanol and adding thissolution to a solution of chitosan in aqueous n-propanol.

As described above, compositions of the invention comprising twolipophilic drugs A and B can be prepared by the method above or by adifferent method. In one embodiment, the two drugs A and B areinterwoven in combination with the same polymeric entity by the abovemethod, producing the dry powder containing the drugs A-B-polymerscomplex, and both drugs undergo thermal behavior modification asdefined. In another embodiment, each of the two drugs is interwovenseparately with the same or different polymeric entity by the abovemethod, producing one dry powder containing the drug A-polymers complexand another dry powder containing the drug B-polymers complex, which arethen mixed, and in which each of the drugs undergo thermal behaviormodification as defined. In a third embodiment, drug A is interwovenwith the polymeric entity by the above method and undergoes thermalbehavior modification as defined, while drug B is not formulated andsimply mixed with the dry powder containing the drug A-polymers complexand drug B does not undergo thermal behavior modification.

An important step in the method of the invention is the drying of thepolymers-lipophilic active compound clear and homogeneous solution, thusobtaining a powder consisting of polymers-lipophilic active compoundcomplex particles having a hydrophobic-hydrophilic gradient to ensuresolubilization. Contrary to the drying process described in U.S. Pat.No. 6,696,084, the method of the present invention is carried out on aclear and homogeneous solution of the polymers-lipophilic drug complexand does not use phospholipid surface active substance(s) nor a bulkingagent such as sucrose to stabilize the lipophilic drug against particlesize growth and agglomeration.

Any conventional method known for drying solutions such as, but notlimited to, spray drying, evaporation by heating under vacuum, andfreeze drying can be used according to the invention. In one morepreferred embodiment of the invention, the powder composition isprepared by the spray drying method.

Upon contact with water or a biological fluid inside the body the powderobtained after spray drying according to the invention is converted intoa colloidal dispersion that contains particles with size in thenanoscale range. For example, about 70% of the particles may have a sizeless than 2000 nm, preferably less than 1500 nm, less than 1200 nm andmore preferably less than 1000 nm.

In the method of the invention, when an amphiphilic and a hydrophilicpolymer are used to form the composition with the drug, the weakinteraction between the two polymers and between the two polymers andthe drug occurs even in the initial organic solvent-water mixture. Asthis medium is not a good solvent for the hydrophilic polymer and forthe hydrophobic drug, both of them can be stabilized via complexationwith the amphiphilic polymer. In the same way, when two amphiphilicpolymers of different hydrophobic-hydrophilic balances are used to formthe composition, the weak interaction between the two polymers occurs inthe organic solvent-water mixture. As this medium is not a good solventfor the amphiphilic polymer which is more hydrophilic, the latter can bestabilized via complexation with the amphiphilic polymer which is morehydrophobic

The spray-drying process ensures a strengthening of the interactionsbetween the polymers themselves and between the polymers and thelipophilic active compound, and this step is thus essential for thepreparation of the polymers-lipophilic active compound complex of theinvention. In the course of drying, a gradual enrichment of the solventmixture with water occurs, thus the self-assembly polymers-lipophilicactive compound complex is formed mostly in an aqueous environment.

Although we do not wish to be bound by any particular theory, it appearsthat the method of the invention provides for “fixation” andstabilization of the lipophilic active compound/drug within thepolymeric entity in such a way that the active compound/drug interactswith the hydrophobic components of the amphiphilic polymer complex andthe hydrophilic components orient themselves outward towards the aqueousmedia, ensuring the solubilization of the lipophilic activecompound/drug.

Introduction of the dried powder into water or aqueous medium does notnecessitate a reorganization of the polymers-drug complex system, as thecomplex disperses itself in the same manner as it was formed. In contactwith water or with a biological fluid in the body, nanodispersions areobtained that comprise nanosized particles of the polymers-lipophilicdrug complex. These factors facilitate rapid dissolution, immediaterelease and improved bioavailability of the lipophilic drug.

In the compositions of the present invention, the lipophilic drugs havemodified physico-chemical properties as compared to the bulk crystallinestarting product and appear not to be pure particles of the drug coatedby polymers, but rather a complex between the drug and the two or morepolymers formed via self-assembly. The distinction between thecompositions of the present invention and those described in the priorart is furthered by a built-in hydrophobic-hydrophilic gradient, whichmaintains integrity and internal order upon dispersion in water andfacilitates release into aqueous media. This combination of theproperties results in optimal characteristics of immediate release and ahigh bioavailability of the lipophilic drug.

It is a finding of the present invention that for the formulation toexhibit superior characteristics as described above one of the polymersmust be amphiphilic (A) and the other may be either amphiphilic (B) withdifferent balance of hydrophobic and hydrophilic segments in the polymerchain than polymer (A), or hydrophilic (C).

The polymer weight ratio is selected so that the interaction between thetwo polymers produces a polymeric entity that interacts with thelipophilic drug at an optimal polymer to lipophilic drug weight ratio insuch a way as to bring the lipophilic drug to the modified thermalbehavior with decreased enthalpy of melting or decrease of both enthalpyand temperature of melting of the lipophilic drug. In this context, itshould be considered that for a higher bioavailability of the lipophilicdrug, it might not be sufficient to reduce its particles to a nanosize.Besides the nanosized particles, the degree of modification of the drugphysico-chemical properties is important: the highest bioavailability isachieved by the highest modification. For example, for loading 25% oflipophilic drug, the ratio between the amphiphilic and the hydrophilicpolymer (or the amphiphilic polymer with a higher hydrophilicity) shouldbe 2:1. For a higher concentration of lipophilic drug, this ratio maynot be suitable and a higher proportion of the amphiphilic polymer maybe needed. If a lower concentration of lipophilic drug is loaded, ahigher degree of melting enthalpy and melting temperature depression canbe achieved when the proportion of the amphiphilic polymer in thepolymeric entity is lower.

As defined herein, when a composition of the invention comprises two orthree amphiphilic polymers, they should have differenthydrophobic-hydrophilic balances. According to the invention, thepolymers-lipophilic drug formulations have a hydrophobic-hydrophilicgradient running from the hydrophobic range (due to the lipophilic drugand the hydrophobic portion of the amphiphilic polymer of lowerhydrophilicity) to the hydrophilic range (due to the hydrophilic polymeror the hydrophilic portion of the amphiphilic polymer having higherhydrophilicity).

The design of the polymeric entity is based on interactions between theamphiphilic polymer with the hydrophilic polymer or with an amphiphilicpolymer of different hydrophobic-hydrophilic balance. Non-covalent bondsare formed between the polymers and said bonds include donor-acceptorand/or electrostatic interactions and hydrogen bonding. The ratiobetween the two polymers amphiphilic:hydrophilic can be from 0.1:0.9 to0.9:0.1 (more amphiphilic polymer is preferred in order to get a largerdegree of melting enthalpy depression), and the loading of thelipophilic drug into the polymer mixture is about 5-50%. In thiscontext, formulations of the prior art using only one amphiphilicpolymer or only one hydrophilic polymer, do not allow for creation of ahydrophobic-hydrophilic gradient which enables stable solid dispersionand other optimal characteristics (Examples 2, 3 and 10). Thecompositions of the invention consisting of the polymers-lipophilic drugcomplex powder obtained by the method of the invention are stable duringat least twelve months, as shown in Example 13 herein below. When thepowder is dispersed in water or in an aqueous environment such as abiological fluid in the body, a colloidal dispersion with nanosizedparticles is obtained.

For prediction of the components—lipophilic active substance andpolymers—interactions and creation of the hydrophilic-hydrophobicgradient of the polymers with the active compound, the solubilityparameters for the components of the composition of the invention can becalculated. The solubility parameter is a tool that can be used forscreening polymer-polymer and polymer-active compoind interactions asdescribed by Hildebrand et al. (Hildebrand, J H, Scott R L, TheSolubility of Non-electrolytes. Reinhold, 3^(rd) edition.,1949, NewYork). In recent years, several research groups have applied solubilityparameters in order to predict drug-polymer miscibility or compatibilityand correlate this with performance-related characteristics of drugdelivery systems (see, for example, Wu C, McGinty J W. 1999.Non-traditional plasticizatioin of polymeric films. Int. J Pharm177:15-27; Sears J K, Touchette N W. 1982. Plasticizers. In: Mark H F,Othmer D F, Overberger C G, Seaborg G T, editors. Kirk-OthmerEncyclopedia of Chemical Technology, Vol. 18. New York: Wiley, pp111-182).

The total and partial solubility parameters that are identified withcohesion energy density can be calculated and compared. It is generallyaccepted that for compatibility or miscibility of materials thedifference between their solubility parameters has to be as small aspossible. For many materials, the cohesive energy is defined not only bydispersion forces, but is dependent on the interaction between the polargroups of the material and on hydrogen bonding. Thus, the totalsolubility parameter (δ) may be divided into three parts correspondingto three types of interactions: δ_(d)—contribution of dispersion forces;δ_(p)—contribution of polar forces, δ_(h)—contribution of hydrogenbonding. All these contributions for the formulation components (drugsand polymers) can help to predict the extent of the drug and amphiphilicpolymer miscibility, and also allow for the selection of propercomponents for induction of the hydrophobic-hydrophilic gradient. Thus,in this way, we can find the polymers which, according to theirsolubility parameters, may serve as a bridge between the lipophilic drugand the amphiphilic and/or hydrophilic polymers or segments and theaqueous media. These polymers allow the design of the integrallipophilic drug-polymers complex with a hydrophobic-hydrophilicgradient.

In accordance with the present invention, the total and partialsolubility parameters for a group of lipophilic active compounds and aselection of amphiphilic and hydrophilic polymers all approved by theFDA for use for oral administration in humans were calculated using theGroup Contribution Method (GCM) (Van Krevelen. 1976, Properties ofPolymers. Elsevier, pp. 129-159) with Molecular Modeling Pro Plussoftware developed by Norgwyn Montgomery Software Inc. and are depictedin the table below. The solubility parameters values of the polymer thatare closest to those of fenofibrate are demonstrated by the PPG block ofPoloxamer (see the δ total). This is indicative that the interactionbetween fenofibrate and this polymer will be the most energeticallyfavorable. Additional polymers having intermediate values, including thePEG block of Poloxamer and other amphiphilic polymers such as PVP,Copovidone, etc., serve as “bridges” to the hydrophilic polymers, whichinclude NaCMC, chitosan, and PVA.

Table of solubility parameters for lipophilic drugs and polymersSolubility Parameters, J^(1/2) × cm^(−3/2) Δd δp Δh δt ActiveFenofibrate 18.48 2.99 3.12 18.98 Compounds Atorvastatin 20.13 4.6611.83 23.81 Itraconazole 23.6 8.45 7.43 26.15 Polymers PVP 22.72 2.849.89 24.94 Copovidone 23.44 4.03 10.14 25.86 Poloxamer PPG 19.17 0.7611.08 22.16 Blocks PEG 20.85 0.99 13.2 24.71 PVA-PVAc 19.15 2.62 22.9129.97 PVA 20.57 2.79 25.53 32.91 Chitosan 21.83 2.95 26.37 34.46 NaCMC10.23 4.96 23.65 26.24

Other drugs such as itraconazole and atorvastatin, according to theirsolubility parameters, can be miscible with a number of differentpolymers, for example PVP, Copovidone, and Poloxamer. In these cases,hydrophilic polymers such as chitosan, NaCMC and PVA are mostappropriate according to the table above.

Therefore, it can be seen that the solubility parameters used in thisway aid the design of formulations with appropriatehydrophobic-hydrophilic gradients. In addition, it can be seen also thatthe use of two or more polymers according to the invention enablesadditional options for selecting suitable hydrophobic-hydrophilic rangesas well as allow a more customized design for active compoundsolubilization.

It should be understood that the term polymeric entity or polymer matrixas used herein does not relate to a pre-prepared polymer construct, butrather to an entity or matrix of the polymers that self-assembles withthe lipophilic drug. When a lipophilic active compound is introducedinto a mixture of polymers according to the invention, it coordinateswith the hydrophobic moieties of the amphiphilic polymer, which is alsointeracted with the hydrophilic polymer, forming a lipophilicdrug-polymers complex thus fixating the lipophilic drug within thepolymeric entity. The polymers-lipophilic drug complex is formed byself-assembly. This is contrary to lipophilic drug particulates known inthe art prepared by milling or similar procedures.

As mentioned before, the interaction between a lipophilic activecompound and hydrophobic moieties of the amphiphilic polymer result inmodification of its physico-chemical properties. Thus, the compositionsof the present invention exhibit significant changes in thermalbehaviour of the lipophilic active compound as compared to the bulkcrystalline compound used as starting material for preparation of thecomposition. They demonstrate a notable decrease of enthalpy of meltingor decrease of both enthalpy of melting and temperature of melting ofthe lipophilic active compound.

Although we do not want to be bound by any specific classification ofthe structure of the compositions of the invention, these compositionsmay include eutectic mixtures, solid solutions or solid suspension withcrystalline, partial and complete amorphous dispersed lipophilic drugphase.

Besides resulting in a modification of the liphophilic active compoundthermal behavior, interaction between the two or more polymers and theliphophilic active compound creates a hydrophobic-hydrophilic gradient,which enables formation of a colloidal nanodispersion upon contact ofthe said composition with aqueous media that in turn facilitatesimmediate release and high bioavailability of the lipophilic activecompound.

In another aspect, the present invention relates to a clear andhomogeneous solution comprising two or more polymers and a lipophilicactive compound in an aqueous solvent consisting of at least 50% byweight water and less than 50% by weight organic solvent in singlephase, that does not undergo sedimentation or precipitation, wherein atleast one of the two or more polymers is an amphiphilic polymer and atleast another of the two or more polymers is either a hydrophilicpolymer or an amphiphilic polymer with a hydrophobic-hydrophilic balancedifferent from the first amphiphilic polymer.

In preferred embodiments, the lipophilic active substance is alipophilic drug, such as, but not limited to, fenofibrate, atorvastatin,itraconazole, clarithromycin, nifedipine, albendazole, hesperitin andtacrolimus, the amphiphilic polymer is as defined hereinbefore,preferably Poloxamer 407, PVP, copovidone, a plant protein or a proteinhydrolisate, and the hydrophilic polymer is as defined hereinbefore,preferably, NaCMC, sodium alginate and chitosan.

The pharmaceutical composition according to the present inventioncomprises the powder consisting of the lipophilic drug-polymers complexof the invention and may further comprise one or more pharmaceuticallyacceptable inert carriers or excipients or both such as binders,diluents, disintegrants, fillers, glidants, lubricants, suspendingagents, sweeteners, flavoring agents, buffers, wicking agents, wettingagents, and effervescent agents.

When a binding agent is present in the composition, preferred bindingagents include polyvinylpyrrolidone, starch, cellulose, e.g. crystallinecellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, starch, saccharose, gelatin, methylcellulose, and the like

When a diluent is present in the composition, preferred diluents includemicrocrystalline cellulose, lactose, dibasic calcium phosphate,mannitol, starch, sorbitol, sucrose, glucose, starch or mixturesthereof.

Disintegrants for use in the invention include crosslinked insolublepolyvinyl pyrrolidone (crosspovidone such as Kollidon CL, KollidonCL-SF), starch and modified starches, croscarmellose sodium (crosslinkedsodium carboxymethy-lcellulose), sodium starch glycolate (e,g,Explotab), alginic acid, alginates, calcium silicate, and mixturesthereof.

Examples of filling agents are microcrystalline cellulose, lactose,mannitol, and starch. Suitable lubricants, including agents that act onthe flowability of the powder to be compressed, are colloidal silicondioxide, talc, stearic acid, magnesium stearate, calcium stearate, andsilica gel.

Glidants can be used to improve the flow characteristics of granulationsand powders by reducing inter-particulate friction and are typicallyadded to pharmaceutical compositions immediately prior to tabletcompression to facilitate the flow of granular material into the diecavities of tablet presses. When used for tablet compression, suitableglidants include: calcium silicate, colloidal silicon dioxide, asbestosfree talc, sodium aluminosilicate, powdered cellulose, microcrystallinecellulose, corn starch, sodium benzoate, calcium carbonate, magnesiumcarbonate, metallic stearates, magnesium lauryl sulfate, and magnesiumoxide.

When a lubricant is present in the composition, a preferred lubricant ismagnesium stearate. Sweeteners, if present, may be any natural orartificial sweetener.

Examples of useful suspending agents include, but are not limited to,surfactants such as stearyltriethanolamine, sodium laurylsulfate (SLS),laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerine monostearate and the like.

A wicking agent, defined as having the ability to draw water into theporous network of a delivery material, may be included in the core of atablet formulation of the invention. The wicking agent can be a swellingor non-swelling wicking agent such as, for example, sodium laurylsulfate, colloidal silicon dioxide, calcium silicate and low molecularweight PVP.

The pharmaceutical composition of the invention comprising thepolymers-lipophilic drug complex and optionally one or morepharmaceutically acceptable inert carriers and/or excipients asdescribed above may be employed as such. However, it is preferable topresent the composition in the form of solid dosage forms such ascapsules, tablets, beads, grains, pills, granulates, granules, powder,pellets, sachets, lozenges, troches, oral suspensions and aerosol.Preferred solid dosage forms include capsules, tablets, pills,granulates, granules, powder, oral suspensions and aerosol.

In one preferred embodiment, the pharmaceutical composition of theinvention is formulated into a tablet.

The compositions of the invention show fast dissolution in testsperformed in accordance with FDA Dissolution Methods for Drug Products.For lipophilic drugs with good permeability, wherein solubility is themain deterrent to achieve good bioavailability, dissolution tests areindicative of solubility and therein bioavailability.

Administration of the composition of the invention is expected to resultin immediate release and improved bioavailability of the lipophilicdrug.

The term “bioavailability” refers to the degree to which the lipophilicdrug becomes available to the target tissue after administration. Asuitable bioavailability for the lipophilic drug composition of theinvention should show that administration of such a composition resultsin a bioavailability that is improved or is at least the same whencompared to the bioavailability obtained after administration of thelipophilic drug raw crystalline powder or of a commercially availableproduct containing the lipophilic drug in the same amounts.

It is also desirable that the lipophilic drug compositions of theinvention show bioequivalency to, and/or improved pharmacokinetic (PK)profiles in comparison to, commercially available lipophilic drugcompositions, namely, that they demonstrate similar or betterpharmacokinetic profiles when given in similar doses under similarconditions. Parameters often used in bioequivalence studies are t_(max),C_(max), AUC_(0-infinity), AUC_(0-t). At least C_(max) and AUCparameters may be applied when determining whether bioequivalence ispresent. The t_(max) denotes the time to reach the maximal plasmaconcentration (c_(max)) after administration; AUC_(0-infinity) or AUCdenotes the area under the plasma concentration versus time curve fromtime 0 to infinity; AUC_(0-t) denotes the area under the plasmaconcentration versus time curve from time 0 to time t, especially,AUC₀₋₂₄ is the area under the plasma concentration versus time curvefrom time 0 to time 24 hr at steady state conditions.

As shown herein in the examples, Table 4 depicts PK plot values (AUC,C_(max)) in rats for a group of fenofibrate formulations of Example 4(formulations 4.1, 4.2, 4.11, 4.12). As can be seen, formulations 4.1and 4.2 show significantly heightened values of AUC and C_(max) whencompared to the commercial micronized fenofibrate In contrast,formulations 4.11 and 4.12 were marginally better than micronizedfenofibrate according to the same parameters. Therefore, thesepreclinical tests enabled us to screen out the less attractiveformulations and focus on the two leading formulations for clinicalstudies as detailed in Example 15.

Table 8 gives a summary of the results for a pilot clinical study forformulations 4.1 and 4.2 as suspensions vs. a Tricor® 145 tablet.Formulation 4.2 showed C_(max) values higher than those for theformulation 4.1. According the main PK parameters (C_(max) and AUC)formulation 4.2 is very similar to the commercial Tricor® 145 tablet.This pilot study therefore indicates that formulation 4.2 could be thefirst choice for clinical studies.

The compositions of the invention comprising the polymers-lipophilicdrug complex are useful for treating a disease, disorder or conditionresponsive to said lipophilic drug.

In one preferred embodiment, the lipophilic drug is fenofibrate and thecompositions of the invention comprising the polymers-fenofibratecomplex are useful for treating a disease, disorder or conditionresponsive to fenofibrate. They are thus useful for treatinghyperlipidemia, a condition characterized by an elevation of lipids(fats) such as cholesterol, cholesterol esters, and triglycerides, inthe bloodstream. Hyperlipidemia is associated with an increased risk ofcoronary heart disease (that can lead to angina pectoris, a heartattack, or both) and to thickening or hardening of the arteries thatsupply blood to the heart muscle. In particular, the compositions can beuseful for treating conditions such as hypercholesterolemia,hypertriglyceridemia, cardiovascular disorders, coronary heart disease,and peripheral vascular disease (including symptomatic carotid arterydisease).

Thus, in one embodiment, the present invention provides a method fortreating hyperlipidemia, which comprises administering to an individualin need a therapeutically effective amount of a pharmaceuticalcomposition of the invention comprising fenofibrate. In preferredembodiments, the method of the invention is useful for treatment ofconditions such as hypercholesterolemia, hypertriglyceridemia,cardiovascular disorders, coronary heart disease, and peripheralvascular disease (including symptomatic carotid artery disease).

In another embodiment, the lipophilic drug is atorvastatin, an inhibitorof 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, useful toreduce the amount of cholesterol and other fatty substances in theblood. Atorvastatin calcium is available as 10, 20, 40 and 80 mg tabletsunder the trademark Lipitor™ (Pfizer Inc.). In one preferred embodiment,the composition of the invention comprises a polymers-atorvastatincomplex, in which the atorvastatin is interwoven with a Poloxamer407-NaCMC polymeric entity. In another embodiment, the composition ofthe invention comprises a polymers-atorvastatin complex, in which theatorvastatin is interwoven with a Poloxamer 407-sodium alginatepolymeric entity.

The atorvastatin compositions are useful for treating hyperlipidemia, acondition characterized by an elevation of lipids (fats) such ascholesterol, cholesterol esters, and triglycerides, in the bloodstream.Hyperlipidemia is associated with an increased risk of coronary heartdisease (that can lead to angina pectoris, a heart attack, or both) andto thickening or hardening of the arteries that supply blood to theheart muscle.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a combination of two cholesterol regulatingdrugs-atorvastatin and fenofibrate in apolymers-fenofibrate/atorvastatin complex in which the fenofibrate andthe atorvastatin are interwoven with a polymeric entity formed byPoloxamer 407 and NaCMC.

Thus, the present invention provides a method for treatinghyperlipidemia, which comprises administering to an individual in need atherapeutically effective amount of a pharmaceutical composition of theinvention comprising a polymers-atorvastatin complex orpolymers-atorvastatin/fenofibrate complex.

In another embodiment, the lipophilic drug is itraconazole, an azolemedicine used to treat fungal infections. It is effective against abroad spectrum of fungi including dermatophytes (tinea infections),yeasts such as candida and malassezia infections, and systemic fungalinfections such as histoplasma, aspergillus, coccidiodomycosis,chromoblastomycosis. Itraconazole is available as 100 mg capsules underthe trademark Sporanox™ (Janssen-Cilag). In one preferred embodiment,the composition of the invention comprises a polymers-itraconazolecomplex, in which the itraconazole is interwoven with a Poloxamer407-sodium carboxymethylcellulose polymeric entity. In another preferredembodiment, the composition of the invention comprises apolymers-itraconazole complex, in which the itraconazole is interwovenwith a Poloxamer 407-chitosan HCl polymeric entity. In a furtherpreferred embodiment, the composition of the invention comprises apolymers-itraconazole complex, in which the itraconazole is interwovenwith a polyvinylpyrrolidinone-protein, preferably corn zein, polymericentity.

In one another embodiment, the lipophilic drug is tacrolimus, amacrolide immunosuppressant administered after allogenic organtransplant to reduce the activity of the patient's immune system and sothe risk of organ rejection. Tacrolimus is available as 0.5, 1.0 and 5.0mg capsules under the trademark Prograf™. In one preferred embodiment,the composition of the invention comprises a polymers-tacrolimuscomplex, in which the tacrolimus is interwoven with a Poloxamer407-NaCMC polymeric entity.

The following examples illustrate certain features of the presentinvention but are not intended to limit the scope of the presentinvention.

EXAMPLES

In the examples below, where the term “ratio” is used, it refers toweight/weight ratio, except the cases where use of the other units isespecially referred in the text.

Materials and Methods:

Materials: Fenofibrate (from ChemAgis, Israel); fenofibrate capsulescontaining micronized fenofibrate (200 mg) for oral administration withfood (from Teva Pharmaceuticals Ltd., Israel); Tricor 145 tablets (fromAbbott Laboratories); Atorvastatin calcium, Nifedipine andClarithromycin (from Teva Pharmaceutical Industries Ltd., Israel);Itraconazole (BP micronized, from Hawkins Inc., USA); Sporanox(granules, from Janssen-Cilag); Tacrolimus (from Fermentek Ltd.,Israel); Resveratrol (from Sigma); hesperitin, albendazole andfenbendazole (from Sito (China) International); Albazen (Rubikon,Byelorussia) [Poloxamer 407 (Lutrol F 127; BASF, Germany); chitosan HCl(from Kraeber GmbH); vinylpyrrolidone-vinylacetate copolymer (CopovidoneK28, Kollidon VA64) and polyvinylpyrrolidone (PVP, Kollidon 30) (fromBASF, Germany); carboxymethylcellulose sodium NaCMC (Aqualon CMC-7L2P,from Aqualon, Hercules Inc.); corn zein (from Sigma); sodium alginate(Protanal SF, from Protan Inc., USA); and polyvinylpyrrolidone (PVP K10,MW 10.000, from Sigma); protein hydrolysate from wheat gluten (HyPep4601 from Sigma); sodium lauryl sulfate, sodium taurocholate, lecithinand aspirin (from Sigma-Aldrich); docusate sodium and sodium benzoate(from Cytec, USA); sodium starch glycolate (Explotab, from JRS Pharma,Germany); lactose (from Alfa Chem. USA); dextrates (from PenwestPharmaceuticals Co., USA), Hypromellose Acetate Succinate (Shin-EtsuAQOAT, from Shin-Etsu, Japan), calcium silicate (from Sigma);1-methyl-2-pyrrolidone (from Riedel-de-Haen); n-propanol (from Sigma).

Methods:

(i) Preparation of the solutions of polymers and active compounds—Theliquid intermediates containing the active compound(s) and the polymerswere prepared using Ekato Unimix LM3 mixer (Ekato Systems GmbH) andperistaltic pump and tubing.

(ii) The spray-drying process was conducted using Mini Spray Dryer B-290of Buchi Labortechnik AG.

(iii) Tablet compression was performed with a Single Punch Tablet PressDP12 —Shanghai Tianxiang & Chentai Pharmaceutical Machinery Co. Ltd.

(iv) The dissolution test was performed in accordance with USPDissolution Method <711> and FDA Dissolution Methods for Drug Productsusing the paddle apparatus Distek model 2100A. The quantification wasperformed using UV spectrophotometer. Appropriate amount of spray driedpowders or tablets as well as control powders or tablets were dissolvedin 1000 ml of 0.05 M water solution of sodium lauryl sulfate, at 37° C.,with rotation speed of 75 rpm and sampling time of 5, 10, 20 and 30 minfor powders or 20, 30, 40 min for tablets.

(v) The tablets disintegration test was performed in accordance with USPDisintegration Method <701>

(vi) Thermal properties of the compositions were studied using standardDSC equipment such as Differential Scanning calorimeter from MettlerToledo, model DSC 820, Aluminum Crucibles standard 40 μl ME-27331,Mettler Toledo Balance MT-15, Sealer Press, Crucible handling setME-119091, and Mettler-Toledo STAR^(e) Software System. The samples(5-10 mg) were heated at a heating rate of 10° C./min from 25° C. to100° C.

(vii) Particle size of the nanodispersions: measurements were performedusing Dynamic Light Scattering (DLS). The method was run on the MalvernZen 3600, Zetasizer-nano series. The samples were prepared by suspendingspray-dried powder in water (0.075-0.1%) at 25-30° C. First, water wasadded to the appropriate amount of the powder and the mixture was leftfor 15 min. Then, the suspension was magnetically stirred during 4 minat 300 rpm and 1 ml of the suspension was transferred to a cuvette formeasurement. The cuvette was incubated inside the instrument during 5min for stabilization prior measurement. A series of at least 5repeating measurements was carried out at 25-30° C. Following parametersare reported from the analysis of volume weighed size distribution:polydispersity index (PDI), the diameter of the main fraction (Z-vol),volume % of main fraction.

(viii) Concentrations of fenofibric acid in rat plasma were determinedby HPLC-UV method using ThermoFinnigan Surveyor Instrument withChromQuest 4.1 software.

(ix) Concentrations of fenofibric acid and resveratrol metabolites inhuman plasma as well as albendazole sulfoxide concentration in pigplasma were determined by validated HPLC-UV methods using Summit DI 6009Dionex (Germany) HPLC system with photodiode array (PDA) detector andChromeleon Version 6.70 software package.

Example 1 Spray-Dried Fenofibrate

Fenofibrate (1.0 g) was dissolved under stirring at 300 rpm in 17.6 glof n-propanol at 45° C. Water (18 g) water was added to the fenofibratesolution at a feeding rate of 1 ml/min, under stirring at 300 rpm and attemperature 45° C. The resultant clear homogeneous solution was placedto the bath at 55° C. and spray dried using Buchi Mini Spray Drier withinlet air temperature 78° C. and outlet temperature 50° C., thusobtaining a powder. This powder was used in comparison studieshereafter.

Example 2 Formulation of Fenofibrate with NaCMC

Drug solution: Fenofibrate (1.0 g) was dissolved under stirring at 300rpm in 89 g of n-propanol at 25° C.

Polymer solution: NaCMC (3.0 g) was dissolved under stirring at 300 rpmin water (100 g) at 43° C.

The drug solution was added to the polymer solution at a feeding rate of2 ml/min, under stirring at 300 rpm and at temperature 45° C., thentemperature was elevated to 56° C. The resultant clear homogeneoussolution was spray dried from hot (50-55° C.) solution, using Buchi MiniSpray Drier with inlet air temperature 98° C. and outlet temperature 64°C., thus obtaining a powder. This powder was used in comparison studieshereafter.

Example 3 Formulation of Fenofibrate with Poloxamer 407

Drug solution: Fenofibrate (0.5 g) was dissolved under stirring at 300rpm in 60 g of n-propanol at ambient conditions.

Polymer solution: Poloxamer 407 (1.5 g) was dissolved under stirring at300 rpm in 75 g of water at ambient conditions.

The drug solution was added to the polymer solution at a feeding rate of2 ml/min, under stirring at 300 rpm at temperature 25° C. The resultantclear homogeneous solution was spray dried using Buchi Mini Spray Drierwith inlet air temperature 100° C. and outlet temperature 64° C., thusobtaining a viscous liquid, which forms a film on the cyclone aftercooling. This film was removed and crushed using mortar and pestle. Thispowder was used in comparison studies hereafter.

Example 4 Fenofibrate Formulations Containing Poloxamer 407 and NaCMC

General procedure for preparation of formulations 4.1-4.14in Table 1:This example presents the matrix design for fenofibrate formulationscomprising different ratios of fenofibrate (FFB), Poloxamer 407 (LutrolF 127) and NaCMC. Loading of fenofibrate in the final dry powder is inthe range of 25-33.3%, and the range of Lutrol F 127 and NaCMC is 22-50%for each. The dry formulations can contain also 2-8% of water. Thecontent of all solids (FFB, Lutrol and NaCMC) in the liquid intermediateis also variable from 2.0% to 6.2% (w/w).

Drug solution: Raw crystalline fenofibrate (FFB) was dissolved understirring at 300 rpm in n-propanol at 25° C.

Polymers solution: NaCMC and Poloxamer 407 were dissolved under stirringat 300 rpm in water at 45° C.

The drug solution was added to the polymers solution at a feeding ratein the range of 2-10 ml/min, under stirring at 300 rpm. The resultantclear homogeneous solutions were spray dried, yielding free-flowingpowders. The mixing and drying parameters are summarized in Table 1.

TABLE 1 Mixing and drying parameters of fenofibrate, Lutrol and NaCMCDrying Mixing parameters Parameters N- Addition Inlet Outlet FormulationFFB Lutrol NaCMC propanol Water Temp Temp temp No. (g) (g) (g) (g) (g)(° C.) (° C.) (° C.). 1 15 15 30 1200 1500 40 120 72 2 15 30 15 12001500 40 110 64 3 45 90 45 1080 1650 55 110 64 4 2 3 3 160 200 30 80 55 50.56 0.48 0.96 40 50 30 100 63 6 0.56 0.72 0.72 40 50 30 80 55 7 0.560.96 0.48 40 50 30 80 52 8 0.60 0.93 0.47 40 50 30 80 54 9 0.60 0.700.70 40 50 30 80 55 10 0.60 0.47 0.93 40 50 30 100 63 11 0.67 0.89 0.4440 50 30 80 52 12 0.67 0.44 0.89 40 50 30 100 62 13 2.67 2.67 2.67 160200 30 100 75 14 0.18 0.57 0.25 50 50 48 96 64

The formulations 1-14 above are referred to in the description and inthe following examples as Examples/formulations 4.1 to 4.14,respectively.

Example 5 Fenofibrate Formulation Containing Poloxamer 407 and SodiumAlginate

Solution A containing fenofibrate and Poloxamer 407: Fenofibrate (0.18g) was dissolved in 16 g n-propanol at ambient conditions under stirringat 300 rpm. Then 5 g of water and 0.20 g of Poloxamer 407 were addedunder stirring.

Solution B containing sodium alginate: Sodium alginate (0.30 g; ProtanalSF) was mixed with 4 ml of 1-propanol at ambient conditions understirring at 300 rpm. Then 35 g of water was added under stirring and themixture was heated up to 65° C. until full dissolution of polymer.

Solution A was added to solution B at a feeding rate of 2 ml/min, understirring conditions (500 rpm) and at temperature 65° C. The resultantclear homogeneous solution was spray dried using Buchi Mini Spray Drierwith inlet air temperature 100° C. and outlet temperature 70° C., thusobtaining a powder.

Example 6 Fenofibrate Formulation Containing Poloxamer 407, PVP andNaCMC

Drug solution: Fenofibrate (0.5 g) was dissolved in 32 g n-propanol atambient conditions under stirring conditions (300 rpm).

Polymers solution: (a) NaCMC (0.5 g) was dissolved in 60 g water understirring (300 rpm) at 50° C.; (b) Poloxamer 407 (0.5 g) was dissolved insolution (a) at 50° C.; (c) PVP 10 kDa (0.5 g) was dissolved in solution(b) at 50° C.; (d) 16 g n-propanol was added to solution (c), and thenthe polymers solution was heated up to 62-63° C., under stirring.

The drug solution was added to the hot polymers solution at a feed rateof 2 ml/min, under stirring at 300 rpm. The resulting transparent,homogeneous solution was spray dried using Buchi Mini Spray Drier withinlet air temperature 100° C. and outlet temperature 60° C., producing apowder.

Example 7 Fenofibrate Formulation Containing PVP, Protein Hydrolysateand NaCMC

Drug solution: Fenofibrate (0.7 g) was dissolved in 32 g n-propanol atambient conditions under stirring conditions (300 rpm).

Polymers solution: (a) NaCMC (0.7 g) was dissolved in 60 g water understirring at 47° C.; (b) 0.3 g protein hydrolysate (wheat gluten) wasdissolved in solution (a) at ambient temperature; (c) PVP 10 kDa (0.3 g)was dissolved in solution (b) at ambient temperature; (d) 16 gn-propanol was added to solution (c), and then the polymer solution washeated up to 67-68° C., under stirring.

The drug solution was added to the hot polymers solution at a feed rateof 2 ml/min, under stirring at 300 rpm. The resulting transparent,homogeneous solution was spray dried using Buchi Mini Spray Drier withinlet air temperature 78° C. and outlet temperature 50° C., producing apowder.

Example 8 Fenofibrate Formulation Containing Copovidone K28 and NaCMC

Drug solution: Fenofibrate (1.25 g) was dissolved in 40 gl n-propanol atambient conditions under stirring conditions (300 rpm).

Polymers solution: (a) NaCMC (1.25 g) was dissolved in 50 g water understirring (300 rpm) at 40-45° C.; and (b) Copovidone K28 (2.50 g) wasdissolved in solution (a) at 50° C.

The drug solution was added to the warm polymers solution (40-45° C.) ata feed rate of 2 ml/min, under stirring at 300 rpm. The resultingtransparent, homogeneous solution was placed to the bath at 55° C. andspray dried using Buchi Mini Spray Drier with inlet air temperature 98°C. and outlet temperature 64-67° C., producing a powder.

Example 9 Fenofibrate Formulation Containing Hypromellose AcetateSuccinate and Protein Hydrolysate

Drug solution: Fenofibrate (0.5 g) was dissolved in 20 g n-propanol atambient conditions under stirring conditions (300 rpm).

Polymers solution: (a) Hypromellose acetate succinate (1.0 g) wasdissolved in 27 gl of n-propanol-water (45:55) mixture under stirring at50° C.; and (b) Protein hydrolysate (1.0 g wheat gluten) was dissolvedin 20 g of water at 56° C.

Drug solution was added to hot (60° C.) solution (a) under magneticstirring (300 rpm) at a feed rate of 2 ml/min producing solution (c).The hot solution (c) was added to hot (60° C.) solution (b) at a feedrate of 2 ml/min under stirring at 300 rpm. The resulting transparenthomogeneous solution was spray dried using Buchi Mini Spray Drier withinlet air temperature 80° C. and outlet temperature 55° C., producing apowder.

Example 10 Particle Size of Aqueous Dispersions Obtained from theFenofibrate Formulations

The powders produced as described in Examples 1-9 have been suspended indeionized water as described in method (vii) of the section Materialsand Methods.

The powders of Examples 1-3 comprising fenofibrate alone or incombination with one sole polymer formed coarse suspensions with largevisible particles. This kind of suspension is unsuitable for DynamicLight Scattering measurement.

The powders of Examples 4-10 comprising fenofibrate-polymersformulations according to invention were converted to colloidaldispersion with particles size in the nanoscale range. The results areshown in Table 2.

TABLE 2 Characteristics of the fenofibrate colloidal dispersions % volof Number of z-vol of the main the main Formulation measurementsfraction, nm PDI fraction Example 4.1 5 628 0.617 90 Example 4.2 10 6690.452 99 Example 4.3 5 916 0.394 100 Example 4.4 10 316 0.514 98 Example4.5 10 405 0.683 84 Example 4.6 15 668 0.580 87 Example 4.7 10 668 0.61795 Example 4.8 10 512 0.480 92 Example 4.9 10 478 0.573 91 Example 4.1010 561 0.563 100 Example 4.11 10 500 0.559 100 Example 4.12 10 481 0.508100 Example 4.13 10 585 0.417 100 Example 4.14 10 605 0.540 100 Example5 15 128 0.384 100 Example 6 5 644 0.378 90 Example 7 5 527 0.591 100Example 8 5 655 0.402 89 Example 9 5 578 0.328 100 z-vol is the meandiameter (in nm) of each definite fraction PDI—polydispersity index

The analysis of dispersions described in the present example show thatonly compositions of the invention possessing thehydrophobic-hydrophilic gradient are able to produce homogeneousnanodispersions. This inherent property ensures improvement in thebioavailability of fenofibrate.

In the Dynamic Light Scattering method, we used two main parameters tocharacterize the colloidal system: the hydrodynamic diameter of theparticles and the width of disdribution (polydispersity). Unimodaldispersions are well characterized by Gaussian distribution with meanparticle diameter (z-average) In the case of multimodal system, a muchmore complex analysis is required. The algorithms used provideinformation about mean diameter, and width and peak mode for eachfraction. The most realistic view of a material distribution tofractions can be obtained from volume weighted particle sizedistribution analysis (Shekunov et al., Particle size analysis inpharmaceutics. Pharmaceutical Research, 2007, vol. 24(2), p. 203).Theterm z-vol is used in this analysis to characterize the mean diameter ofeach definite fraction. PDI is used to characterize the reliability ofparticles size distribution analysis. The values between 0.08 and 0.7belong to a mid-range polydispersity. It is the range trough which theDLS distribution algorithm operates in the best way. The values above0.7 mean that the sample is too polydisperse and not suitable for DLStechnique.

As shown in Table 2, all dispersions of Examples 4-9 demonstratemid-range polidispersity (PDI in the range from 0.08 to 0.7). The highpercentages of main fraction indicate a substantially unimodal(homogeneous) distribution of the nanocolloidal particles dispersion.]

Example 11 Thermal Properties of Fenofibrate Formulations

In order to determine the thermal properties of fenofibrate in thecompositions of the invention, the temperature (T_(melt)) and theenthalpy (ΔH_(melt)) of melting of spray-dried powders obtained in theprevious examples were determined by Differential Scanning calorimetry(DSC) as described in Methods section. These characteristics werecompared to thermograms of starting commercial raw fenofibrate as wellas of commercial fenofibrate drug products. The enthalpy of fenofibratemelting is given in Joule per gram of fenofibrate (J/_(gFF)). Theresults are shown in Table 3.

TABLE 3 DSC of fenofibrate formulations T_(melt) ΔH_(melt) Sample (° C.)(J/g_(FF)) Fenofibrate starting material 81.9 74.3 Microcrystallinefenofibrate 82.8 71.3 Fenofibrate nanoparticulate 77.2 54.6 (Tricor145 ™ crushed tablet) Example 1 (Spray-dried fenofibrate) 81.2 71.8Example 2 78.0 43.9 Example 3 Non-resolved peak of fenofibrate Example4.1 72.0 39.0 Example 4.2 63.6  6.5 Example 4.3 63.7 16.5 Example 4.467.6 24.8 Example 4.5 78.4 43.3 Example 4.6 73.3 34.4 Example 4.7 66.017.3 Example 4.8 68.0 22.3 Example 4.9 75.6 35.8 Example 4.10 78.6 42.8Example 4.11 63.7 21.1 Example 4.12 78.2 52.4 Example 4.13 72.6 38.5Example 4.14 Non-resolved peak of fenofibrate Example 5 69.1 30.5Example 6 71.1 33.4 Example 7 76.8 49.0 Example 8 78.0 11.0 Example 978.0 16.7

As can be seen from Table 3, raw crystalline fenofibrate powder(starting material) exhibits an endothermic peak around 82° C. withmelting enthalpy 74.3 J/g. Commercial micronized (microcrystalline)fenofibrate demonstrates only a minor change of the fenofibrate meltingenthalpy (71.3 J/g). Fenofibrate nanoparticulate produced by millingTricor® 145 tablet (ΔH_(melt)=54.6 J/g) shows a reduction of meltingenergy of only 19.7 J/g. The application of spray-drying process(Example 1) alone leaves fenofibrate almost unchanged (see also FIG. 1).

In contrast, introduction of fenofibrate into the polymers-fenofibratecomplex according to the invention and its interaction with hydrophobicmoieties of the amphiphilic polymer resulted in a significant depressionof the drug fusion peak (ΔH_(melt)). The compositions described inexamples 4.2, 4.3, 4.4, 4.6 to 4.9, 4.11, 5, 6, 8, and 9 demonstrate2-10 fold reduction of enthalpy compared to bulk starting fenofibrateMore specifically, FIG. 2 illustrates this phenomenon and shows 6.8-foldreduction of fenofibrate enthalpy for the solid dispersion described inExample 8.

The maximum degree of interaction between fenofibrate and Poloxamer 407in the ratio 1:3 (Examples 3 and 4.14) results in an extremely strongdepression of the melting point of fenofibrate, overlapping with thepolymer peak, and thus no resolved peak of drug is observed.

The thermotropic profile of the compositions of the invention alsopointed out strong interactions of the fenofibrate with the polymers.The temperature of melting was shifted down from 82-83° C. to 63-73° C.in the examples 4.1 to 4.4, 4.6 to 4.8, 4.11, 4.13, 5, and 6. Morespecifically, FIG. 3 illustrates this phenomenon and shows an 18.3° C.down-shift of melting temperature for the solid dispersion offenofibrate described in Example 4.2 as well as a 11.4-fold reduction offenofibrate enthalpy compared to bulk starting fenofibrate.

Example 12 In Vivo Pharmacokinetics Study in Rats

In vivo studies were conducted for determining the bioavailability ofthe fenofibrate compositions of the present invention relative to thebioavailability of the commercially available micronized fenofibratepowder. The study was designed to determine the correlation betweenphysico-chemical properties of the compositions (particle size andthermal behavior) and their bioavailability.

Preparations comprising fenofibrate formulations obtained in Examples4.1, 4.2, 4.11, 4.12 or micronized fenofibrate were administered orallyas water suspensions to male Sprague-Dawley rats (280-300g; Harlan Inc.,Israel), via a feeding tube (gavage). Water suspensions were prepared 1hr before their administration to rats in concentration 1.5 mg/ml andpulled by a syringe at continuous mixing on a magnet stirrer. Each ratwas administered a single oral dose of 7.5 mg/kg. Administration of thedrug followed overnight fasting, while water was freely available. Bloodsamples were collected from the tail at the following points of time:pre-dosing and 1, 2, 3 and 4 hours post-dosing. Blood concentration offenofibric acid at each point of time was determined by HPLC-UV method(materials and Methods, item ix) and calculated as average for a groupof 5 animals. Pharmacokinetic parameters (C_(max), AUC_(0-4,)C_(maxtest)/C_(maxref), and AUC_(0-4test)/AUC_(0-4ref)) were determinedfor each formulation. The correlation between results and compositionsare shown in Table 4.

TABLE 4 Fenofibric acid pharmacokinetic parameters in rats CompositionFFB:Amp:Hydro Ratio C_(max) AUC_(0-4test)/ Formulation (%) FFB:Amp μg/mlAUC₀₋₄ AUC_(0-4ref) Micronized 6.19 20.7 Fenofibrate Example 25:25:501.00:1.00 20.09 54.6 2.64 4.1 Example 25:50:25 1.00:2.00 20.47 69.2 3.344.2 Example 33.3:44.3:22.3 1.00:1.33 10.89 36.8 1.78 4.11 Example33.3:22.3:44.3 1.00:0.67 7.78 25.5 1.23 4.12

As can be seen from Table 4, all formulations of the inventiondemonstrated a significantly better absorption of fenofibrate into ratblood stream than commercial micronized fenofibrate. In addition, theformulations of Examples 4.1 and 4.2 with loading of 25% fenofibrateshowed better absorption (C_(max)=20.09, 20.47) than formulations ofExamples 4.11; 4.12 with loading of 33.3% fenofibrate Poloxamer 407:NaCMC=1:2, Examples 4.1 and 4.12 or 2:1, Examples 4.2 and 4.11), thepreferable ratio is 2:1, with the excess of Poloxamer 407.

These results teach that the highest bioavailability is correlated withthe most significant depression of both thermal characteristics—enthalpyand temperature, as shown in Table 3 for formulation 4.2.

Example 13 Stability of Spray-Dried Powders

Samples of the spray-dried formulation of 4.2 and 4.3 were stored duringtwelve months (25° C. and 60% RH) and were subjected to a fenofibrateassay, water content, as well as particles size and thermal propertiesmeasurements as described in Methods. The properties of the formulationsafter storage were compared with the initial properties of the material.The results are summarized in Table 5.

TABLE 5 Properties of initial spray dried powders and samples afterstorage Assay Water T_(m) ΔH_(m) Main peak, Compositions (mg/g) (%) (°C.) (J/g_(FFB)) nm(% vol) Example 4.2_(initial) 235.7 4.14 63.6 6.5 669(99)  Example 4.2_(stored) 239.4 4.08 63.1 7.6 812 (100) Example4.3_(initial) 240.2 2.86 63.7 16.5 916 (100) Example 4.3_(stored) 239.13.17 62.9 14.6 847 (90) 

Analysis of the obtained results reveals that the recovery offenofibrate after storage is within 90%-110% of the assay value for theinitial sample; water, fenofibrate melting point and enthalpy and dataof particle size distribution of the formulations after storage differfrom the initial parameters by no more than 20%. Thus, thecharacteristics of the spray-dried powders demonstrate that thecompositions described in the Examples 4.2 and 4.3 are stable understorage at 25±2° C. and 60% RH during at least twelve months.

Example 14 Immediate Release Tablets

The powder materials of the polymers-fenofibrate compositions wereblended with inactive ingredients acting as tablet fillers, diluents,disintegrants, wicking agents or lubricants. The mixtures werecompressed into tablets of 145 mg strength. The compositions of tablets(A-F) and results of their dissolution tests are given in Tables 6 and7, respectively.

TABLE 6 Compositions of the fenofibrate tablets A B C D E F Ingredient(mg) (mg) (mg) (mg) (mg) (mg) Powder of Example 4.3 592 592 592 592 592592 Lactose 200 206 112 60 Dextrates 200 160 Sodium Starch Glycolate 40Calcium Silicate 80 54 Sodium Lauryl Sulfate 16 33 Sodium Docusate 21Sodium Benzoate 5 Magnesium Stearate 8 8 8 2 2 Tablet total weight (mg)800 800 800 800 800 767

TABLE 7 Dissolution profiles of tablets A-E in % of dissolvedfenofibrate Minutes A B C D E F 20 41.7 45.3 28.7 29.0 28.3 24.1 30 58.864.3 43.1 46.0 43.6 39.3 40 73.2 78.3 56.3 58.2 56.3 50.7 60 93.7 95.977.3 78.1 76.8 69.5

In order to predict the behavior of the tablets in vivo, disintegrationtests were carried out in gastrointestinal fluids (GIF). Tablet B wasplaced into simulated gastric fluid (SGF, pH=1.2) for 1 h and after thisinto simulated intestinal fluid (SIF, pH=6.8) for additional two hours.The tablet remained intact after exposure to SGF, while in the SIFtablet disintegrated completely for 2 h. The colloidal dispersionobtained after disintegration showed the same particles size asdispersion formed by the initial powder of formulation 4.3.

Example 15 Pharmacokinetic Study of the Fenofibrate Formulations inPowder Form in Humans

A bioavailability test of the formulations 4.1 and 4.2 and Tricor® 145mg was carried out in humans as follows. A randomized three-waycrossover comparative bioavailability study was carried out with asingle 145 mg dose in 12 healthy volunteers using the formulations ofExamples 4.1 and 4.2 and Tricor® 145 mg. The study was done in thefasted state. The formulations 4.1 and 4.2 were administered as oralsuspensions (50 ml) and Tricor® 145 mg as a tablet. A 10-day washoutbetween periods was maintained before dosing the next product. Bloodsamples were collected in each period at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 23, 47, 71 and 95 hours in order to characterize drug absorptionand elimination. These samples were analyzed for fenofibric acid contentby a HPLC-UV validated method.

The pharmacokinetic parameters of the tests of the compositions 4.1 and4.2 of the invention and the reference product Tricor®145 absorptionsare shown below in Table 8.

TABLE 8 Fenofibrate pharmacokinetic parameters in humans AUC_(inf)AUC_(0-95 h) T_(max) C_(max) C_(maxtest)/ AUC_(inf. test)/ FormulaTion(μg · h/ml) (μg · h/ml) (h) (μg/ml) C_(maxref) AUC_(inf. ref)Tricor145 ™ 127.0 121.6 2.2 8.25 SD = 42.6 SD = 38.7 SD = 0.83 SD = 1.63Example 121.7 116.2 2.2 6.28 0.76 0.96 4.1 SD = 42.1 SD = 39.5 SD = 0.80SD = 1.24 Example 121.0 116.2 3.0 7.16 0.87 0.95 4.2 SD = 41.0 SD = 37.4SD = 0.82 SD = 1.16

The pharmacokinetic parameters shown in Table 8 first demonstrate thatthere is no difference in the amount of drug absorbed when thesuspensions of the inventions 4.1 or 4.2 are administrated versuscommercial Tricor® 145 mg tablet (see AUC results). Second, the datashow that the rate of fenofibrate absorbance is higher for theformulation 4.2 (87% of reference C. result) than for formulation 4.1(76% of reference C_(max) result).

As can be concluded from this preliminary study, the high degree ofpolymer-drug interactions, which express themselves in the thermalproperties and ability to form the nanodispersion, are key factors thatimpact the rate of fenofibrate absorption. The higher C_(max) result offormulation 4.2 in humans could be predicted from its physicochemicalproperties enabling higher absorption into the rat bloodstream.

Example 16 Combination of fenofibrate and aspirin in one capsule

Method A: 590 mg of the composition described in the example 4.3comprising 145 mg of fenofibrate was blended with 75 mg of aspirin andfilled to a capsule.

Method B: 590 mg of the composition described in the example 4.3comprising 145 mg of fenofibrate was dry granulated using a rollercompactor. 75 mg of aspirin was blended with 100 mg of lactose and thendry granulated using roller compactor. Granules containing fenofibrateand granules containing aspirin were blended and filled to capsule.

Example 17 Combination of Fenofibrate and Aspirin in one Tablet

Method A: 590 mg of the composition described in the example 4.3comprising 145 mg of fenofibrate is blended with 75 mg of aspirin, 100mg of lactose and 8 mg of magnesium stearate and compressed to tablet.

Method B: 590 mg of the composition described in the example 4.3comprising 145 mg of fenofibrate is dry granulated using rollercompactor. 75 mg of aspirin is blended with 100 mg of lactose and 8 mgof magnesium stearate and the mixture is dry granulated using rollercompactor. Granules containing fenofibrate and granules containingaspirin are blended and compressed to tablet.

Method C: Granules containing fenofibrate (145 mg) obtained according tothe method B are filled to the tablet mold as the first layer and thengranules containing aspirin (75 mg) obtained according to the method Bare filed to the tablet mold as the second layer. The two tablet layersare compressed using appropriate conventional tools and a suitablebilayer tabletting press, to form a bilayered tablet.

Example 1 8 Spray-Dried Atorvastatin

0.3 g of Atorvastatin was dissolved under stirring at 300 rpm in amixture of 21.6 g n-propanol and 17 g water at 40° C. The resultantclear homogeneous solution was placed to the bath at 55° C. and spraydried, using Buchi Mini Spray Drier with inlet air temperature 108° C.and outlet temperature 71° C., thus obtaining a powder. This powder wassuspended in deionized water as described in the Method section, item(vii), and formed coarse suspensions with large visible particles. Thiskind of suspension is unsuitable for Dynamic Light Scatteringmeasurement.

No atorvastatin melting peak was found on the DSC thermogram afterpreparation, confirming an amorphous form of the drug. However, afterstorage of six months some broad peak in the range of 116-183° C.appeared. This peak can be attributed to the beginning of thecrystallization process.

Example 19 Atorvastatin Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Atorvastatin (0.5 g) was dissolved in 48 g of1-methyl-2-pyrrolidone at ambient conditions by stirring at 300 rpm.

Polymers solution: NaCMC (1.0 g) and Lutrol 127F (0.5 g) were dissolvedby stirring at 300 rpm in water (50 g) at 38° C.

The drug solution was added to the polymers solution at a feeding rateof 10 ml/min, under stirring at 300 rpm at 38° C. The resultant clearhomogeneous solution was spray dried using Buchi Mini Spray Drier inletair temperature 110° C. and outlet temperature 69° C., yielding apowder, which readily dissolves in water media. No atorvastatin meltingpeak was found on the DSC thermogram. The thermogram of the formulationstored for six months showed the same result. A dissolution test showedthat 85% of atorvastatin is released to phosphate-buffered saline (PBS),pH=6.9, during 14 min.

Example 20 Atorvastatin Formulation Containing Poloxamer 407 and SodiumAlginate

Solution A: 0.120 g Atorvastatin was dissolved in a mixture of 16 g1-propanol and 5 ml water at 65° C., under stirring at 300 rpm, followedby addition of 0.05 g Lutrol under stirring.

Solution B: 0.300 g Sodium alginate (Protanal SF) was mixed with 3.2 g1-propanol at ambient conditions by stirring at 300 rpm. Then, 35 gwater was added under stirring and the mixture was heated up to 65° C.until full dissolution of the polymer.

Solution A was added to solution B at a feeding rate of 10 ml/min, understirring at 500 rpm and at a temperature of 65° C. To the obtained clearviscous solution (122 csp), 20 ml n-propanol and 28 ml water were added.The resultant clear homogeneous solution was spray dried using BuchiMini Spray Drier with inlet air temperature 115° C. and outlettemperature 70° C., yielding a powder of polymers-atorvastatin complexcomprising amorphous atorvastatin and freely dissolvable in water. Noatorvastatin melting peak was found on the DSC thermogram. Thethermogram of the formulation stored for six months showed the sameresult. A dissolution test showed that 91% of atorvastatin is releasedto PBS, pH=6.9, during 30 min.

Example 21 Fenofibrate/Atorvastatin Formulations Containing Poloxamer407 and NaCMC. General Procedure for Preparation of the Formulations21.1-21.3

Drug solution: Appropriate amounts of fenofibrate and atorvastatincalcium (see Table 9) were dissolved in 48 g 1-methyl-2-pyrrolidone atambient conditions.

Polymers solution: Appropriate amounts of NaCMC and of Poloxamer 407(see Table 9) were dissolved by stirring at 300 rpm in 50 g water at 45°C.

The drug solution was added to hot polymers solution (68° C.) withfeeding rate 2 ml/min under stirring at 300 rpm. The resultingtransparent hot (68° C.) solutions were spray dried using Buchi MiniSpray Drier with inlet air temperature 110° C. and outlet temperature70° C., producing the powders, which upon contact with water convertedto colloidal dispersion.

General Procedure for Preparation Formulation 21.4 and 21.5

Drug solution: Appropriate amounts of atorvastatin calcium waredissolved in a mixture of 22.5 g of n-propanol-water (44:56/v:v) at50-60° C. under stirring at 300 rpm, followed by addition of appropriateamounts of fenofibrate to the mixture.

Polymers solution: Appropriate amounts of NaCMC were dissolved in 25 gwater at 50-60° C. under stirring at 300 rpm, followed by addition ofappropriate amounts of Poloxamer 407. In the next step, 20 g n-propanolwere added to the water solution of the polymers and the mixture washeated to 70° C.

The hot (60° C.) drug solution was added to hot polymers solution (70°C.) with feeding rate 2 ml/min under stirring at 300 rpm. The resultingtransparent hot (70° C.) solutions were spray dried using Buchi MiniSpray Drier with inlet air temperature 110° C. and outlet temperature66° C. producing the powders, which upon contact with water converted tocolloidal dispersion.

Table 9 presents the compositions of five different formulations offenofibrate and atorvastatin in NaCMC and Poloxamer 407 and Table 10presents the particle size of the water dispersions obtained from thefive formulations.

TABLE 9 Composition of formulations of fenofibrate/atorvastatincontaining Poloxamer 407 and NaCMC Fenofibrate Atorvastatin NaCMC LutrolFormulation (g) (g) (g) (g) Example 21.1 0.435 0.119 1.110 0.555 Example21.2 0.435 0.060 0.990 0.495 Example 21.3 0.435 0.030 0.930 0.465Example 21.4 0.435 0.030 0.465 0.930 Example 21.5 0.435 0.119 0.5551.110

TABLE 10 Characteristics of the fenofibrate/atorvastatin formulations %vol of Number of z-vol of the main the main Formulation measurementsfraction, nm PDI fraction Example 21.1 10 1157 0.660 100 Example 21.2 12919 0.624 100 Example 21.3 5 1694 0.324 70 Example 21.4 5 645 0.308 100Example 21.5 5 1856 0.216 100

The results show that all powder formulations 21.1-21.5 can givecolloidal dispersions in the range 600-2000 nm upon contact with water,but only compositions 21.2 and 21.4 provide nanosized particles.

Example 22 Thermal Properties of Fenofibrate/Atorvastatin Formulations

In order to determine the thermal properties of the compositions of theinvention comprising fenofibrate and atorvastatin, the temperature andthe enthalpy of melting of spray-dried powders were determined byDifferential Scanning calorimetry (DSC) as described in Methods section.These characteristics were compared to thermograms of startingcommercial raw fenofibrate as well as of commercial fenofibrate drugproducts. The results are shown in Table 11. The thermograms of thecombined drug formulation show no peak of atorvastatin. The enthalpy offenofibrate melting is given in Joule per gram (J/g) of fenofibrate.

TABLE 11 DSC of fenofibrate/atorvastatin formulations T_(melt) ΔH_(melt)Sample (° C.) (J/g) Fenofibrate starting material 81.9 74.3Microcrystalline fenofibrate 82.8 71.3 Fenofibrate nanoparticulate 77.254.6 (Tricor 145 ™ crushed tablet) Example 1 (Spray-dried fenofibrate)81.2 71.8 Example 21.1 61.9 16.0 Example 21.2 69.9 29.7 Example 21.364.9 19.4 Example 21.4 70.9 4.30 Example 21.5 60.1 2.85

As can be seen from Table 11, the starting raw crystalline fenofibratepowder exhibits an endothermic peak around 82° C. with melting energy74.3 J/g. Commercial microcrystalline fenofibrate demonstrates only someminor changes of the fenofibrate melting enthalpy (71.3 J/g).Nanoparticulate of fenofibrate produced by milling (Tricor® 145) showsreduction of melting energy only of 19.7 J/g. By applying thespray-drying process alone (Example 1), the characteristics offenofibrate remain almost unchangeable. In contrast, the introduction offenofibrate into the polymer(s)-fenofibrate/atorvastatine complexaccording to the invention and their interaction with hydrophobicmoieties of the amphiphilic polymer result in a significant depressionof the fenofibrate fusion peak. Pharmaceutical compositions described inexamples 21.1-21.5 demonstrate 2-19 folds reduction of enthalpy comparedwith initial fenofibrate. The thermotropic profile of solids in theseexamples also pointed out strong interactions of the fenofibrate withthe polymers. The temperature of melting is shifted down from 82-83° C.to 60-71° C.

Thus, it can be concluded that for compositions comprising a combinationof two lipophilic drugs, each lipophilic compound demonstrates the samethermal properties as in a composition comprising the individual drugs.(Examples 11 and 19)

Example 23 Itraconazole Formulation Containing Poloxamer 407 andChitosan

Solution A: Itraconazole (0.2 g) was dissolved in 15.2 g 1-propanol at65° C. under stirring at 300 rpm. Then 5 g water and 0.25 g Lutrol 127Fwere added while stirring.

Solution B: Chitosan.HC1 (0.350 g) was mixed with 2.4 g 1-propanol, 15 gwater were added while stirring, and the mixture was heated up to 60° C.until full dissolution of the polymer.

Solution A was added to solution B at a feeding rate of 10 ml/min, understirring at 500 rpm and at a temperature of 60° C. The resultantsolution was spray dried using Buchi Mini Spray Drier with inlet airtemperature 115° C. and outlet temperature 70° C., thus yielding apowder, which upon contact with water converted to a colloidaldispersion with a particles size of 655 nm.

Raw itraconazole crystalline powder exhibits an endothermic peak around169.7° C. with melting energy of 84.4 J/g. In the DSC thermogram of thisexample, the melting temperature of itraconazole was observed at 159.0°C. and the melting enthalpy was 42.5 J/g. In the thermogram of theformulation stored for six months, the melting temperature ofitraconazole was observed at 158.4° C. and the melting enthalpy was 42.5J/g.

Example 24 Itraconazole Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Itraconazole (0.5 g) was dissolved in 39 g acetonitrileand 3 g acetic acid at 60° C. under stirring at 300 rpm.

Polymers solution: NaCMC (0.5 g) and Lutrol 127F (1.0 g) were dissolvedunder stirring at 300 rpm in water (45 g) at 55° C.

The drug solution was added to the polymers solution at a feeding rateof 10 ml/min, under stirring at 300 rpm at 65° C. The resultingtransparent solution was spray dried using Buchi Mini Spray Drier withinlet air temperature 125° C. and outlet temperature 79° C., thusyielding a free-flowing powder comprising 2-10 μm particles, which uponcontact with water converted to colloidal dispersion with a particlessize of 1108 nm.

Raw itraconazole crystalline powder exhibits an endothermic peak around169.7° C. with melting energy of 84.4 J/g. In the DSC thermogram of thisexample, the melting temperature of itraconazole was observed at 155.6°C. and the melting enthalpy was 21.9 J/g. In the thermogram of theformulation stored for six months, the melting temperature ofitraconazole was observed at 154.4° C. and the melting enthalpy was 24.6J/g.

Example 25 Itraconazole Formulation Containing PVP and Corn Zein

Solution A: Itraconazole (0.20 g) and 0.2 g corn zein were dissolved ina mixture of 18 g 1-propanol and 2.5 g water at 60° C., under stirringat 300 rpm.

Solution B: 0.1 g PVP (Kollidon® 30, BASF) was dissolved in 20 gdeionized water under stirring at 300 rpm and the mixture was heated upto 60° C. until full dissolution of the polymer.

The solution A was added to solution B at a feeding rate of 10 ml/min,under stirring at 500 rpm, at 60° C. The obtained warm (52° C.)opalescent homogeneous solution was spray dried using Buchi Mini SprayDrier with inlet temperature 80° C. and outlet temperature 53° C., thusyielding off-white powder comprising 2-10 μm particles, which uponcontact with water converted to colloidal dispersion with a particlessize of 919 nm.

No itraconazole melting peak was found on the DSC thermogram. Thethermogram of the formulation stored for six months showed the sameresult.

Example 26 Dissolution Profile of Itraconazole

Portions of spray-dried powders obtained in Examples 23-25 as well ascontrol powders containing 100 mg itraconazole were dissolved in 900 mlof a 0.05 M solution of sodium lauryl sulfate, at 37° C., at a rotationspeed of 100 rpm and sampling time of 10, 30, 60 and 90 min.

The dissolution profiles of itraconazole are reported in Table 12. Ascan be seen, the itraconazole compositions of Examples 24 and 25 showedsignificantly more rapid dissolution as compared to raw itraconazolematerial. The dissolution of these compositions was similar toitraconazole from Sporanox™ granules.

TABLE 12 Dissolution profile in % of dissolved itraconazole Sample 10min 30 min 60 min 90 min Itraconazole raw powder 7.8 23.2 35.9 44.5Sporanox ™ 64.0 100.0 100.0 100.0 Example 23 10.0 37.3 58.6 63.7 Example24 57.6 73.4 75.7 80.5 Example 25 70.8 75.4 77.2 80.9

Example 27 Tacrolimus Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Tacrolimus (0.09 g) was dissolved in 8 gl n-propanol atambient conditions by stirring at 300 rpm.

Polymers solution: NaCMC (0.09 g) and Lutrol 127F (0.18 g) weredissolved by stirring at 300 rpm in water (10 g) at 40° C.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 45° C. The resultant clearhomogeneous solution was dried using Buchi rotavapor, thus yielding apowder that upon contact with water converted to colloidal dispersionwith a particles size of 910 nm.

Raw tacrolimus crystalline powder exhibits an endothermic peak around135.3° C. with melting energy of 60.1 J/g. In the DSC thermogram of thisexample, the melting temperature of tacrolimus was observed at 118.5° C.and the melting enthalpy was 52.2 J/g.

Example 28 Nifedipine Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Nifedipine (0.50 g) was dissolved in 40 g n-propanol atambient conditions by stirring at 300 rpm.

Polymers solution: NaCMC (0.50 g) and Lutrol 127F (1.00 g) weredissolved by stirring at 300 rpm in 50 g water at 45° C.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 55° C. The resultant clearhomogeneous solution was spray dried using Buchi spray drier thusyielding a powder, which upon contact with water converted to acolloidal dispersion with a particles size of 1190 nm.

Raw nifedipine crystalline powder exhibits an endothermic peak around172.4° C. with melting energy of 113.4 J/g. In the DSC thermogram ofthis example, the melting temperature of nifedipine was observed at140.9 ° C. and the melting enthalpy was 8.4 J/g.

Example 29 Clarithromycin Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Clarithromycin (0.50 g) was dissolved in 40 g n-propanolat 35 ° C. by stirring at 300 rpm.

Polymers solution: NaCMC (0.50 g) and Lutrol 127F (1.00 g) weredissolved by stirring at 300 rpm in water (50 g) at 45° C.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 57° C. The resultant clearhomogeneous solution was dried using Buchi spray drier thus yielding apowder, which upon contact with water convered to colloidal dispersionwith a particles size of 836 nm.

Raw clarithromycin crystalline powder exhibits an endothermic peakaround 227.6° C. with melting energy of 70.2 J/g. In the DSC thermogramof this example, the melting temperature of clarithromycin was observedat 207.9° C. and the melting enthalpy was 40.1 J/g.

Example 30 Albendazole Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Albendazole (0.50 g) was dissolved in 44.5 gtetrahydrofuran at 35 ° C. by stirring at 300 rpm.

Polymers solution: NaCMC (0.50 g) and Lutrol 127F (1.00 g) weredissolved by stirring at 300 rpm in water (50 g) at 45° C.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 38° C. The resultant clearhomogeneous solution was dried using Buchi spray drier thus yielding apowder, which upon contact with water converted to colloidal dispersionwith a particles size of 555 nm.

Raw albendazole crystalline powder exhibits an endothermic peak around215 ° C. with melting energy of 209.7 J/g. In the DSC thermogram of thisexample, the melting temperature of albendazole was observed at 161.1°C. and the melting enthalpy was 31.2 J/g.

The formulation of this example demonstrated significantly higherdissolution rate in 0.05 M sodium lauryl sulfate than that of rawalbendazole: 73.2% of formulated albendazole was dissolved after 15 min,while only 16.6% of raw material was released at the same point of time.

Example 31 Pharmacokinetic Study of Formulated Albendazole OralSuspension in Pigs

A randomized four-way parallel comparative bioavailability study wascarried out with a single administration of two dose level (5mg/kg and10 mg/kg) using the formulation of Example 30 and the commercialveterinary drug Albazen containing the same active compound in groups of5 pigs (20 kg). The study was done in the fasted state. All formulationswere administered as oral suspensions (2 and 4 ml). Blood samples werecollected in each period at 0, 3, 9 and 24 hours in order tocharacterize drug absorption and elimination. These samples wereanalyzed for albendazole sulfoxide content by a HPLC-UV validatedmethod.

Pharmacokinetic parameters (C_(max), AUC_(0-24,)C_(max test)/C_(max ref), and AUC_(0-24test)/AUC_(0-24ref)) weredetermined for each formulation. The results are shown in Table 13 andFIG. 4.

TABLE 13 Albendazole-SO pharmacokinetic parameters in pigs C_(max)AUC₀₋₂₄ C_(max test)/ AUC_(0-24test)/ Formulation μg/ml μg · h/mlC_(max ref) AUC_(0-24ref) Albazen (5 mg/kg) 0.98 12.54 Example 30 (5mg/kg) 1.91 24.66 1.95 1.97 Albazen (10 mg/kg) 0.92 13.13 Example 30 (10mg/kg) 3.08 36.45 3.35 2.77

Example 32 Fenbendazole Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Fenbendazole (0.25 g) was dissolved in 22.5 g of dimethylsulfoxide at ambient conditions by stirring at 300 rpm.

Polymers solution: NaCMC (0.25 g) and Lutrol 127F (0.50 g) weredissolved by stirring at 300 rpm in water (25 g) at 40° C.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 80° C. The resultant clearhomogeneous solution was dried using Buchi spray drier thus yielding apowder, which upon contact with water converted to a colloidaldispersion with a particles size of 892 nm.

Raw fenbendazole crystalline powder exhibits an endothermic peak around239° C. with melting energy of 166.3 J/g. In the DSC thermogram of thisexample, the melting temperature of fenbendazole was observed at 203.7°C. and the melting enthalpy was 8.9 J/g.

Example 33 Hesperetin Formulation Containing Poloxamer 407 and NaCMC

A mixture of NaCMC (1.5 g) and Lutrol 127F (3 g) was dissolved bystirring at 300 rpm in water (64 g) at ambient conditions, followed byaddition of ethanol (44 g). Hesperetin (1.5 g) was added to the polymerssolution and this mixture was heated up to 64° C. until full dissolutionof hesperetin. The resultant clear homogeneous solution was dried usingBuchi spray drier thus yielding a powder, which upon contact with waterconverted to a colloidal dispersion with a particles size in nanoscalerange.

Raw hesperetin crystalline powder exhibits an endothermic peak around231 ° C. with melting energy of 166.2 J/g. In the DSC thermogram of thisexample, no peak was observed which could correspond to hesperetin.

Example 34

Resveratrol Formulation Containing Poloxamer 407 and NaCMC

Drug solution: Resveratrol (1.5 g) was dissolved in 32 g ethanol atambient conditions by stirring at 300 rpm.

Polymers solution: NaCMC (1.5g) and Lutrol 127F (3.0 g) were dissolvedby stirring at 300 rpm in water (64 g) at ambient conditions.

The drug solution was added to the polymers solution at a feeding rateof 2 ml/min, under stirring at 300 rpm at 60° C. The resultant clearhomogeneous solution was dried using Buchi spray drier thus yielding apowder, which upon contact with water converted to colloidal dispersionwith a particles size in nanoscale range.

Raw resveratrol crystalline powder exhibits an endothermic peak of267.4° C. with melting energy of 253.6 J/g. In the DSC thermogram ofthis example, the melting temperature of resveratrol was observed at201.2° C. and the melting enthalpy was 12.4 J/g.

Example 35 Resveratrol Formulation Containing Poloxamer 407 and SodiumAlginate

Solution A: Resveratrol (1.5 g) was dissolved in 23.4 g ethanol atambient conditions under stirring at 300 rpm. Then 5 g water and 3 gPoloxamer 407 were added under stirring and all solids were dissolved.

Solution B: Sodium alginate (1.5 g) was mixed with 8.8 g ethanol atambient conditions under stirring at 300 rpm. Then 59 g water were addedunder stirring and the mixture was heated up to 68° C. until fulldissolution of polymer.

Solution A was added to solution B at a feeding rate of 2 ml/min understirring conditions (300 rpm) and at temperature 60° C. The resultantclear homogeneous solution was spray dried using Buchi Mini Spray Drierwith inlet air temperature 90 ° C. and outlet temperature 64° C., thusobtaining a powder, which upon contact with water converted to colloidaldispersion with a particles size in nanoscale range.

Raw resveratrol crystalline powder exhibits an endothermic peak of267.4° C. with melting energy of 253.6 J/g. In the DSC thermogram ofthis example, the melting temperature of resveratrol was observed at202.8 ° C. and the melting enthalpy was 12.9 J/g.

Example 36 Dissolution of Resveratrol Raw Powder and ResveratrolFormulations in Model Fasted Duodenal Solution

The Model Fasted Duodenal Solution (MFDS) was prepared as follows: amixture of sodium chloride (3.093 g), sodium hydrophosphate (1.719 g)and sodium taurocholate (0.8065 g) was dissolved in deionized water (300g) using ultrasonic bath. Lecithin (0.2925 g) was dissolved in 2 mlmethylene chloride and added to the buffered solution of sodiumtaurocholate. The resulting emulsion was stirred for 5 min and thenmethylene chloride was evaporated under vacuum. The obtained clearmicellar solution was adjusted to the volume of 500 ml by deionizedwater.

For the test procedure, the test resveratrol formulations or rawresveratrol powder (10 mg) were placed into 2 ml microcentrifuge tubeand MFDS (1.8 ml) was added to the each tube. The tubes were gentlyshaken (about 50 rpm) at 37° C. and samplings were taken at 10, 20, 40,60 and 120 min. For this purpose, the tubes were vortexed at the highestspeed for 60 seconds and then centrifuged at 13 000 G for 60 seconds.The solid-free supernatant (0.4 ml) was mixed with 0.4 ml diluent (30%water adjusted to pH 2.5 with phosphoric acid and 70% acetonitrile) andthis solution was inserted into an HPLC instrument for determination ofresveratrol concentration.

The results of dissolution of raw resveratrol and resveratrolformulations in MFDS are summarized in Table 13 and in FIG. 5.

TABLE 13 Comparative dissolution rate of resveratrol raw powder vs.resveratrol formulations in MFDS Concentration of resveratrol (μg/ml)Sample 10 min 20 min 40 min 60 min 120 min Resveratrol 76.65 103.15119.3 121.05 155.6 raw powder Example 34 510.7 451.9 630.4 641.2 647.4Example 35 529.05 529 454.1 589.9 511.7

This example clearly confirms that formulated resveratrol has highdissolution rate and saturated solubility as compared to raw resveratrolpowder.

Example 37 Pharmacokinetic Study of the Resveratrol Formulations inPowder Form in Humans

A randomized two-way crossover comparative bioavailability study wascarried out with a single 500 mg dose using the formulation of Example35 and raw resveratrol powder in 12 healthy volunteers. The study wasdone in the fasted state. The formulations 35 and raw resveratrol powderwere administered as oral suspensions (100 ml). A 7-day washout betweenperiods was maintained before dosing the next product. Blood sampleswere collected in each period at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8,10, 12, 23 and 36 hours in order to characterize drug absorption andelimination. These samples were analyzed for resveratrol and itsmetabolites content by a HPLC-UV validated method.

1. A solid composition that forms a colloidal nanodispersion uponcontact with aqueous media, said composition comprising at least onelipophilic active compound and two or more polymers, in which the atleast one lipophilic active compound is interwoven with a polymericmatrix formed by the two or more polymers, at least one of the two ormore polymers is an amphiphilic polymer and at least another of the twoor more polymers is either a hydrophilic polymer or an amphiphilicpolymer with a hydrophobic-hydrophilic balance different from the firstamphiphilic polymer, and each of the at least one lipophilic activecompound has modified physico-chemical properties as compared to thesame lipophilic active compound used as the starting product for thepreparation of the composition, wherein i. each of the at least onelipophilic active compound has modified physico-chemical propertiesrepresented either by decreased enthalpy of melting or by both decreasedenthalpy and decreased temperature of melting as compared to the samebulk starting crystalline lipophilic active compound; ii. said polymericmatrix is not crosslinked and no covalent interaction occurs between thetwo or more polymers and between the polymers and the at least onelipophilic active compound; and said lipophilic active compound or asalt, isomer, ester, ether or other derivative thereof is selected fromacetylcholinesterase inhibitors, analgesics and nonsteroidalantiinflammatory agents, anthelminthics, antiacne agents, antianginalagents, antiarrhythmic agents, anti-asthma agents, antibacterial agents,anti-benign prostate hypertrophy agents, anticancer agents andimmunosuppressants, anticoagulants, antidepressants, antidiabetics,antiemetics, antiepileptics, antifungal agents, antigout agents,antihypertensive agents, antiinflammatory agents, antimalarials,antimigraine agents, antimuscarinic agents, antineoplastic agents,antiobesity agents, antiosteoporosis agents, antiparkinsonian agents,antiproliferative, antiprotozoal agents, antithyroid agents, antitussiveagent, anti-urinary incontinence agents, antiviral agents, anxiolyticagents, appetite suppressants, beta-blockers, cardiac inotropic agents,chemotherapeutic drugs, cognition enhancers, contraceptives,corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunctionimprovement agents, expectorants, gastrointestinal agents, histaminereceptor antagonists, hypnotics, immunosuppressants, keratolytics, lipidregulating agents, leukotriene inhibitors, macrolides, muscle relaxants,neuroleptics, nutritional agents, opiod analgesics, protease inhibitors,sedatives, sex hormones, stimulants, vasodilators, essential fattyacids, non-essential fatty acids, proteins, peptides, sugars, vitamins,nutraceuticals, natural agents, or mixtures thereof. 2-4. (canceled). 5.The composition according to claim 1, wherein said lipophilic activecompound or a salt, isomer, ester, ether or other derivative thereof isselected from the group consisting of: (i) acetylcholinesteraseinhibitors selected from the group consisting of donepezil, tacrine, andpyridostigmine; (ii) analgesics and nonsteroidal antiinflammatory agents(NSAIA) selected from the group consisting of aloxiprin, auranofin,azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal,etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid,mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone,phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol,tramadol and tromethamine, (iii) anthelminthics selected from the groupconsisting of albendazole, bephenium hydroxynaphthoate, cambendazole,dichlorophen, fenbendazole, ivermectin, mebendazole, oxamniquine,oxfendazole, oxantel embonate, praziquantel, pyrantel embonate andthiabendazole; (iv) antiacne agents selected from the group consistingof isotretinoin and tretinoin; (iv) antianginal agents selected from thegroup consisting of amyl nitrate, glyceryl trinitrate (nitroglycerin),isosorbide dinitrate, isosorbide mononitrate, pentaerythritoltetranitrate, and ubidecarenone (coenzyme Q10); (v) antiarrhythmicagents selected from the group consisting of amiodarone HCl, digoxin,disopyramide, flecainide acetate and quinidine sulfate; (vi) anti-asthmaagents selected from the group consisting of zileuton, zafirlukast,terbutaline sulfate, montelukast, and albuterol; (vii) antibacterialagents, including antibiotics, selected from the group consisting ofalatrofloxacin, azithromycin, aztreonum, baclofen, benzathinepenicillin, cefixime, cefuraxime axetil, cinoxacin, ciprofloxacin HCl,clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin,doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin,imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid,nitrofurantoin, norfloxacin, ofloxacin, phenoxymethyl penicillin,rifabutin, rifampicin, rifapentine, sparfloxacin, spiramycin,sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide,sulphadiazine, sulphafurazole, sulpha-methoxazole, sulphapyridine,tetracycline, trimethoprim, trovafloxacin, and vancomycin; (vii)anti-benign prostate hypertrophy (BPH) agents selected from the groupconsisting of alfuzosin, doxazosin, phenoxybenzamine, prazosin,terazosin and tamulosin; (viii) anticancer agents and immunosuppressantsselected from the group consisting of abarelix, aldesleukin,alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide,amsacrine, anastrozole, arsenic trioxide, asparaginase, azacitidine,azathioprine, BCG Live, bevacuzimab (avastin), bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, busulfan, calusterone, camptothecin,capecitabine, carboplatin, carmustine, celecoxib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cyclosporin, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa,daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral),doxorubicin HCl, dromostanolone propionate, ellipticine, enlimomab,estramustine, epirubicin, epoetin alfa, erlotinib, estramustine,etoposide, exemestane, filgrastim, floxuridine fludarabine, fulvestrant,gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelinacetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinibmesylate, interferon alfa-2a, interferon alfa-2b, irinotecan,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, megestrol acetate, melphalan, mercaptopurine, mesna,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, mofetilmycophenolate, nandrolone, nelarabine, nilutamide, nofetumomab,oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate,pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine,quinacrine, rasburicase, rituximab, sargramostim, sirolimus, sorafenib,streptozocin, sunitinib maleate, tacrolimus, tamoxifen citrate,temozolomide, teniposide, testolactone, thioguanine, thiotepa,topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracilmustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate,and zoledronic acid; (ix) anticoagulants selected from the groupconsisting of cilostazol, clopidogrel, dicumarol, dipyridamole,nicoumalone, oprelvekin, phenindione, ticlopidine, and tirofiban; (x)antidepressants selected from the group consisting of amoxapine,bupropion, citalopram, clomipramine, fluoxetine HCl, maprotiline HCl,mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl,trazodone HCl, trimipramine maleate, and venlafaxine HCl; (xi)antidiabetics selected from the group consisting of acetohexamide,chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride,glyburide, miglitol, pioglitazone, repaglinide, rosiglitazone,tolazamide, tolbutamide and troglitazone; (xii) antiepileptics selectedfrom the group consisting of beclamide, carbamazepine, clonazepam,thotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin,methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,phenacemide, phenobarbitone, phenytoin, phensuximide, primidone,sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;(xiii) antifungal agents selected from the group consisting ofamphotericin, butenafine HCl, butoconazole nitrate, clotrimazole,econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole,ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate,oxiconazole, terbinafine HCl, terconazole, tioconazole and undecenoicacid; (xiv) antigout agents selected from the group consisting ofallopurinol, probenecid and sulphinpyrazone; (xv) antihypertensiveagents selected from the group consisting of amlodipine, benidipine,benezepril, candesartan, captopril, darodipine, dilitazem HCl,diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate,felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan,isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine,nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril,reserpine, terazosin HCl, telmisartan, and valsartan; (xvi) antimalarialagents selected from the group consisting of amodiaquine, chloroquine,chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl,pyrimethamine and quinine sulfate; (xvii) antimigraine agents selectedfrom the group consisting of dihydroergotamine mesylate, ergotaminetartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifenmaleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;(xviii) antimuscarinic agents selected from the group consisting ofatropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine,mepenzolate bromide, oxyphencyclimine HCl, and tropicamide (xix)antiparkinsonian agents selected from the group consisting ofbromocriptine mesylate, lysuride maleate, pramipexole, ropinirole HCl,and tolcapone; (xx) antiprotozoal agents selected from the groupconsisting of atovaquone, benznidazole, clioquinol, decoquinate,diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone,metronidazole, nimorazole, nitrofurazone, ornidazole and tinidazole;(xxi) antithyroid agents selected from the group consisting ofcarbimazole and propylthiouracil; (xxii) antitussive agent such asbenzonatate; (xxiii) antiviral agents selected from the group consistingof abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine,nelfinavir, nevirapine, ritonavir, saquinavir, and stavudine; (xxiv)anxiolytics, sedatives, hypnotics and neuroleptics selected from thegroup consisting of alprazolam, amylobarbitone, barbitone, bentazepam,bromazepam, bromperidol, brotizolam, butobarbitone, carbromal,chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothixene,clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol,ethinamate, flunanisone, flunitrazepam, triflupromazine, flupenthixoldecanoate, fluphenthixol decanoate, flurazepam, gabapentin, haloperidol,lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine,methaqualone, methylphenidate, midazolam, molindone, nitrazepam,olanzapine, oxazepam, pentobarbitone, perphenazine pimozide,prochlorperazine, propofol, pseudoephedrine, quetiapine, risperidone,sertindole, sulpiride, temazepam, thioridazine, triazolam, zolpidem, andzopiclone; (xxv) beta.-blockers selected from the group consisting ofacebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol,oxprenolol, pindolol and propranolol; (xxvi) cardiac inotropic agentsselected from the group consisting of anrinone, digitoxin, digoxin,enoximone, lanatoside C and medigoxin; (xxvii) corticosteroids selectedfrom the group consisting of beclomethasone, betamethasone, budesonide,cortisone acetate, desoxymethasone, dexamethasone, fludrocortisoneacetate, flunisolide, fluocortolone, fluticasone propionate,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone; (xxviii) diuretics selected from the group consisting ofacetazolamide, amiloride, bendroflumethiazide, bumetanide,chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone,spironolactone and triamterene; (xxix) gastrointestinal agents selectedfrom the group consisting of bisacodyl, cimetidine, cisapride,diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide,mesalazine, nizatidine, omeprazole, ondansetron HCl, pantoprazole,rabeprazole sodium, ranitidine HCl, and sulphasalazine; (xxx) histamineH₁- and H₂-receptor antagonists selected from the group consisting ofacrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine,clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine,dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizineHCl, oxatomide, and terfenadine; (xxxi) keratolytic agents selected fromthe group consisting of acetretin, calciprotriene, calcifediol,calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids,targretin, and tazarotene; (xxxii) lipid regulating/hypolipidemic agentsselected from the group consisting of atorvastatin, bezafibrate,cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin,gemfibrozil, hesperetin, lovastatin, pravastatin, probucol, andsimvastatin; (xxxiv) muscle relaxants selected from the group consistingof cyclobenzaprine, dantrolene sodium and tizanidine HCl; (xxxv) opioidanalgesics selected from the group consisting of codeine,dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol,methadone, morphine, nalbuphine and pentazocine; (xxxvi) sex hormonesselected from the group consisting of clomiphene citrate, cortisoneacetate, danazol, dehydroepiandrosterone, ethynyl estradiol,finasteride, fludrocortisone, fluoxymesterone, medroxyprogesteroneacetate, megestrol acetate, mestranol, methyltestosterone, mifepristone,norethisterone, norgestrel, oestradiol, conjugated estrogens,progesterone, rimexolone, stanozolol, stilbestrol, testosterone andtibolone; (xxxvii) stimulants selected from the group consisting ofamphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;(xxxviii) nutraceutical agents selected from the group consisting ofcalcitriol, carotenes, chrysin, dihydrotachysterol, flavonoids,hesperetin resveratrol, jasmonates, -lipoic acid, lutein, lycopene,essential fatty acids, non-essential fatty acids, naringenin,phytonadiol, quercetin, vitamins including vitamin A, vitamin B₂,vitamin D and derivatives, vitamin E, and vitamin K, coenzyme Q10(ubiquinone), plant extracts, and minerals.
 6. The composition accordingto claim 1, wherein i. said amphiphilic polymer is selected from thegroup consisting of polyethylene oxide (PEO), PEO derivatives,poloxamers, poloxamines, polyvinylpyrrolidones, hydroxypropyl cellulose,hypromellose, hypromellose phthalate, hypromellose acetate succinate,polyacrylates, polymethacrylates, polyethylene glycol (PEG) copolymers,PEO/polypropylene glycol copolymers, PEG-modified starches, vinylacetate-vinyl pyrrolidone copolymers, polyacrylic acid copolymers,polymethacrylic acid copolymers, plant proteins and proteinhydrolysates; and ii. said hydrophilic polymer is selected from starch,sodium carboxymethylcellulose, hydroxyethylcellulose, polyvinyl alcohol,sodium alginate, chitosan, and carrageenan.
 7. (canceled)
 8. Thecomposition according to claim 1, wherein; i. two polymers form thepolymeric matrix, one of the polymers is an amphiphilic polymer selectedfrom Poloxamer 407 or vinylpyrrolidone-vinyl acetate copolymer, and theother polymer is a hydrophilic polymer selected from sodiumcarboxymethylcellulose, sodium alginate or chitosan, or ii. twoamphiphilic polymers form the polymeric matrix, said two amphiphilicpolymers are selected from polyvinylpyrrolidone and a plant protein suchas corn zein, or hypromellose acetate succinate and protein hydrolysate.9-11. (canceled)
 12. The composition according to claim 1, wherein threepolymers form the polymeric matrix, and either i. one of the threepolymers is an amphiphilic polymer and the other two polymers arehydrophilic polymers; or, ii. two of the three polymers are amphiphilicpolymers with different hydrophobic-hydrophilic balance, selected frompolyvinylpyrrolidone and a plant protein hydrolysate, orpolyvinylpyrrolidone and Poloxamer 407, and the third polymer is ahydrophilic polymer, such as sodium carboxymethylcellulose. 13-14.(canceled)
 15. The composition according to claim 5, wherein thecomposition is; i. a pharmaceutical composition comprising at least onelipophilic drug selected from fenofibrate, atorvastatin, clarithromycin,itraconazole, nifedipine, albendazole, or tacrolimus; ii. a veterinarycomposition comprising at least one lipophilic drug selected fromalbendazole, fenbendazole or itraconazole; or iii. a nutraceuticalcomposition, comprising at least one nutraceutical selected fromresveratrol or hesperetin.
 16. (canceled)
 17. The pharmaceuticalcomposition according to claim claim 15, comprising fenofibrate as thesole lipophilic drug, and either: i. two polymers forming the polymericmatrix selected from an amphiphilic polymer, such as Poloxamer 407, anda hydrophilic polymer selected from sodium carboxymethylcellulose orsodium alginate, or ii. three polymers forming the polymeric matrix.18-38. (canceled)
 39. The nutraceutical composition according to claim15, comprising resveratrol as the lipophilic nutraceutical and twopolymers forming the polymeric matrix, wherein one of the polymers is anamphiphilic polymer, preferably Poloxamer 407, and the other is ahydrophilic polymer, preferably sodium carboxymethylcellulose, sodiumalginate or chitosan. 40-41. (canceled)
 42. The pharmaceuticalcomposition according to claim 15, comprising two lipophilic drugsselected from fenofibrate and atorvastatin. 43-46. (canceled)
 47. Thepharmaceutical composition according to claim 15, further comprising oneor more pharmaceutically acceptable carriers, excipients or both whereinsaid composition is formulated for oral administration into a dosageform, selected from the group consisting of capsules, tablets, beads,grains, pills, granulates, granules, powder, pellets, sachets, troches,oral suspensions and aerosol, preferably tablets. 48-54. (canceled) 55.The nutraceutical composition according to claim 39 further comprisingone or more nutraceuticals, nutritional agents, acceptable carriers,excipients or a mixture thereof. 56-74. (canceled)